Retinoid compound, preparation method therefor, intermediates thereof and application thereof

ABSTRACT

Disclosed are a retinoid compound, a preparation method therefor, intermediates thereof and an application thereof. The retinoid compound I of the present invention has a good tumor growth inhibition rate.

The present application is a divisional of U.S. application Ser. No.16/083,879 filed Sep. 10, 2018, which is a 371 application ofPCT/CN2017/071922 filed Jan. 20, 2017, which claims the benefit of theChinese Patent Application No. CN201610141143.3 filed on Mar. 11, 2016and the Chinese Patent Application No. CN201610310944.8 filed on May 11,2016. The contents of all of the above applications are incorporatedherein by reference in its entirety.

FIELD OF INVENTION

The present invention relates to a retinoid compound, a preparationmethod, an intermediate and a use thereof.

PRIOR ARTS

Tazarotene is a retinoid drug with RAR subtype selectivity (J Am AcadDermatol. 1997, 37, S12), mainly used for the treatment of topicalepithelial hyperplasia skin (psoriasis, psoriasis, acne, etc.).Tazarotene is an ethyl ester prodrug, which is metabolized by enzyme toTazarotenic acid as the carboxyl-type active metabolite in vivo.Tazarotenic acid can selectively interact with RARβ and RARγ receptors,and has a certain effect on RARβ, but has a weak effect on RXR.

Content of the Present Invention

The technical problem to be solved in the present invention is toovercome the poor inhibition rate of Tazarotene on tumor cells, thus thepresent invention provides a retinoid compound, a preparation method, anintermediate and a use thereof. The compound of the present inventionexhibits a better inhibition rate on tumor cells.

The present invention provides a compound represented by formula I, anenantiomer, a diastereomer or a pharmaceutically acceptable saltthereof,

wherein, U is CR^(9a) or N; V is CR^(9b) or N; X is CR^(9c) or N; W isCR^(9d) or N;

in the definition of U, V, X and W, each of R^(9a), R^(9b), R^(9c) andR^(9d) is independently hydrogen, hydroxy, nitro, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C₁-C₆ alkyl (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl),C₁-C₆ alkyl substituted with halogen (the halogen can be fluorine,chlorine, bromine or iodine; the C₁-C₆ alkyl can be methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl; the“C₁-C₆ alkyl substituted with halogen” such as trifluoromethyl), C₁-C₆alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, pentoxy or hexoxy), —NR¹⁰R¹¹,

or —COOR¹⁴;

each of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently hydrogen or C₁-C₆alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl or hexyl);

the bond connecting AE, EG or GZ is independently a single bond or adouble bond; when A, E, G or Z connects to two single bonds, thecorresponding A, E, G and Z are independently —(CR²R³)—, —C(═O)—,—(NR⁴)—, —(N→O)—, —O—, —S—, —S(═O)— or —SO₂—; when A, E, G or Z connectsto a single bond and a double bond, the corresponding A, E, G and Z areindependently —(CR⁵)═ or —N═;

each of R², R³, R⁴ and R⁵ is independently hydrogen, hydroxy, halogen(e.g. fluorine, chlorine, bromine or iodine), C₁-C₆ alkyl (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl orhexyl), C₂-C₆ alkenyl (e.g. vinyl or propenyl), C₁-C₆ alkyl substitutedwith halogen (the halogen can be fluorine, chlorine, bromine or iodine;the C₁-C₆ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl or hexyl; the “C₁-C₆ alkyl substituted withhalogen” such as trifluoromethyl), C₁-C₆ alkoxy (e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy orhexoxy), C₁-C₆ acyl (e.g. acetyl or formyl), C₆-C₁₀ aryl (e.g. phenyl)or “C₃-C₆ heteroaryl having 1 to 2 heteroatoms selected from the groupconsisting of oxygen, sulfur and nitrogen” (e.g. pyridinyl orpyrimidinyl);

m is 0, 1, 2 or 3;

when there are more than one substituents of R¹, the substituents areidentical or different; R¹ is hydrogen, hydroxy, nitro, cyano, halogen(e.g. fluorine, chlorine, bromine or iodine), C₁-C₆ alkyl (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl orhexyl), C₁-C₆ alkyl substituted with halogen (the halogen can befluorine, chlorine, bromine or iodine; the C₁-C₆ alkyl can be methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl orhexyl; the “C₁-C₆ alkyl substituted with halogen” is for exampletrifluoromethyl), C₁-C₆ alkoxy (e.g. methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy), —NR⁶R⁷or —COOR⁸;

each of R⁶, R⁷ and R⁸ is independently hydrogen or C₁-C₆ alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,pentyl or hexyl);

Y is —CN, —COOR¹⁵ or —CO₂NHR¹⁶;

each of R¹⁵ and R¹⁶ is independently hydrogen, C₁-C₆ alkyl (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl orhexyl), C₂-C₆ alkenyl (e.g. vinyl or propenyl) or C₁-C₆ acyl (e.g.formyl or acetyl);

the compound represented by formula I is not

Preferably, A, E, G together with Z can form the ring selected from thegroup consisting of

R², R³ and R⁵ are defined as above.

Preferably, in compound I, at least one (e.g. one, two, three or four)of U, V, X and W is N atom.

More preferably, in compound represented by formula I, when two of U, V,X and W are N atoms, the compound represented by formula I can beselected from the group consisting of

wherein, A, E, G, Z, R¹, m, Y, R^(9a), R^(9b), R^(9c) and R^(9d) aredefined as above.

Preferably, in compound A, when Y is —COOR⁵, R¹⁵ is hydrogen or ethyl.

Preferably, in compound A, Z is —(CR²R³)—, —S—, —S(═O)— or —SO₂—; morepreferably, A, E, G together with Z form the ring selected from thegroup consisting of

R² and R³ are defined as above.

More preferably, in compound A, when Y is COOH, Z is —S—.

More preferably, in compound A, when Y is COOEt, Z is —(CR²R³)—, —S(═O)—or —SO₂—.

Preferably, in compound B, when Y is —COOR¹⁵, R¹⁵ is methyl or ethyl.

Preferably, in compound B, Z is —(CR²R³)—, —S— or —S(═O)—; morepreferably, A, E, G together with Z form the ring selected from thegroup consisting of

R² and R³ are defined as above.

More preferably, in compound B, when Y is COOMe, Z is —(CR²R³)—, R² andR³ are defined as above.

More preferably, in compound B, when Y is COOEt, Z is —(CR²R³)— or —S—,R² and R³ are defined as above.

More preferably, in compound B, when Y is CN, Z is —(CR²R³)—, —S— or—S(═O)—, R² and R³ are defined as above.

Preferably, in compound C, when Y is —COOR¹⁵, R¹⁵ is hydrogen or ethyl.

Preferably, in compound C, Z is —(CR²R³)—, —S— or —S(═O)—; morepreferably, A, E, G together with Z form the ring selected from thegroup consisting of

R² and R³ are defined as above.

More preferably, in compound C, when Y is COOH, Z is —S—.

More preferably, in compound C, when Y is COOEt, Z is —(CR²R³)—, —S— or—S(═O)—, R² and R³ are defined as above.

Preferably, in compound presented by formula I, when one of U, V, X andW is N atom, the compound represented by formula I can be selected from

wherein, A, E, G, Z, R¹, m, Y, R^(9a), R^(9b), R^(9c) and R^(9d) aredefined as above.

Preferably, in compound D, when Y is —COOR¹⁵, R¹⁵ is hydrogen or ethyl.

Preferably, in compound D, Z is —(CR²R³)—; more preferably, A, E, Gtogether with Z form

R² and R³ are defined as above.

Preferably, in compound E, Y is CN.

Preferably, in compound E, Z is —(CR²R³)—; more preferably, A, E, Gtogether with Z form

R² and R³ are defined as above.

Preferably, in compound represented by formula I, when U is CR^(9a), Vis CR^(9b), X is CR^(9c), and W is CR^(9d), the compound represented byformula I is as compound F:

wherein, A, E, G, Z, R¹, m, Y, R^(9a), R^(9b), R^(9c) and R^(9d) aredefined as above.

Preferably, in compound F, at least one (e.g. one, two, three or four)of R^(9a), R^(9b), R^(9c) and R^(9d) is not hydrogen.

Preferably, in compound F, when Y is —COOR¹⁵, R¹⁵ is hydrogen, methyl orethyl.

Preferably, in compound F, Z is —(CR²R³)—, —S—, —S(═O)— or —SO₂—; morepreferably, A, E, G together with Z form the ring selected from thegroup consisting of

R², R³ and R⁵ are defined as above.

More preferably, the compound represented by formula I is selected fromthe group consisting of

The present invention also provides a preparation method for thecompound represented by formula I, which comprises conducting a couplingreaction with compound II and III to give compound I;

wherein, X¹ is halogen (e.g. fluorine, chlorine, bromine or iodine).

In the preparation method for the compound represented by formula I, thecondition of the coupling reaction can be conventional conditions in theart, preferably that under an atmosphere of a protective gas (e.g.argon), in an organic solvent (e.g. DMF), in the presence of a catalyst(e.g. Pd/Cu catalyst; the “Pd/Cu catalyst” such as Pd(PPh₃)₂Cl₂ and CuI)and a base (e.g. diisopropylamine or triethylamine), conducting acoupling reaction with compound II and III to give compound I.

The compound represented by formula I can be converted to analogue witha different functional group by flexible functional group conversion andadjustment (including but not limited to esterification, esterhydrolysis, reduction, acylation, oxidation, etc.).

The preparation method for the compound represented by formula I canfurther comprise conducting a deprotection reaction of compound IV togive compound III;

In the preparation method for the compound III, the condition of thedeprotection reaction can be conventional conditions in the art,preferably that in an organic solvent (e.g. tetrahydrofuran), in thepresence of a base (e.g. tetra-n-butylammonium fluoride), conducting adeprotection reaction of compound IV to give compound III.

The preparation method for the compound represented by formula I canfurther comprise conducting a coupling reaction with compound V andtrimethylethynyl silane to give compound IV;

wherein, X² is halogen (e.g. bromine or iodine).

In the preparation method for the compound represented by formulalV, thecondition of the coupling reaction can be conventional conditions in theart, preferably that under an atmosphere of a protective gas (e.g.argon), in an organic solvent (e.g. DMF), in the presence of a catalyst(e.g. Pd/Cu catalyst; the “Pd/Cu catalyst” such as Pd(PPh₃)₂Cl₂ and CuI)and a base (e.g. diisopropylamine or triethylamine), conducting acoupling reaction of compound V with trimethylethynyl silane to givecompound IV.

The present invention also provides a compound represented by formulaII, III, IV or V,

wherein, A, E, G, Z, R¹, m, X¹, Y, U, V, X and W are defined as above.

The present invention further provides a use of the compound representedby formula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the treatmentof a primary tumor. The tumor includes, but is not limited to, melanoma,esophageal cancer, gastric cancer, lung cancer, liver cancer, ovariancancer, colon cancer, kidney cancer, cholangiocarcinoma, breast canceror prostate cancer.

The present invention also provides a use of the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the preventionand/or the treatment of a metastatic tumor. The tumor includes, but isnot limited to, melanoma, esophageal cancer, gastric cancer, lungcancer, liver cancer, ovarian cancer, colon cancer, kidney cancer,cholangiocarcinoma, breast cancer or prostate cancer.

The present invention also provides a use of the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the preventionand/or the treatment of leukemia and/or lymphoma.

The present invention also provides a use of the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the useselected from the group consisting of animal fetal growth, internalenvironment stability, vision, morphogenesis, skin aging and celldifferentiation control.

The present invention also provides a use of the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the treatmentof psoriasis.

The present invention also provides a use of the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof in manufacturing a medicament for the treatmentof acne.

The present invention also provides a pharmaceutical composition, whichcomprises the compound represented by formula I, the enantiomer, thediastereomer or the pharmaceutically acceptable salt thereof, and apharmaceutically carrier.

The route of administration of the pharmaceutical composition can beoral administration, injection and topical administration. When thepharmaceutical composition is administered by oral administration, thedosage form of the composition includes, but is not limited to, tablets,capsules, suspensions, solutions, emulsions, microspheres, nanospheresuspensions, controlled release niosomes or polymer niosomes. When thepharmaceutical composition is administered by injection, the dosage formof the composition solutions or suspensions for infusion or injection.Generally, the compounds of the present invention are daily administeredat a dose of about 0.01 mg/kg to 100 mg/kg based on the body weight, thedose is divided into 1-3 part for administration. The concentration ofthe compounds of the present invention used systemically is generally0.01% to 10% (weight), preferably 0.01% to 1% (weight) based on theweight of the composition. When the pharmaceutical composition isadministered by topical administration, the pharmaceutical compositionis especially used for the treatment of skin and mucosal diseases, canbe used in the form of liquid, paste or solid, especially ointments,creams, solutions, gels, sprays, suspensions and adhesives. The form canalso be microspheres, nanosphere suspensions, controlled releaseniosomes, polymer niosomes, gel patch or polymer patch. Theconcentration of the compounds which are administered by topicaladministration is usually 0.001% to 10% (weight), preferably 0.01% to 1%(weight) based on the total weight of the composition.

The pharmaceutical composition can also comprise inert additives, or apharmaceutically active ingredient that is positively associated withthe pharmaceutical composition, or a mixture of such ingredients. Ofcourse, the person skilled in the art will be careful to select theabove optional compound to be added into the above composition, ensuringthat the advantage of the present invention is not or basicly notaffected by the predetermined additive.

In the present invention, the “C₁-C₆ acyl” refers to an alkyl acyl grouphaving 1 to 6 carbon atoms, for example the acyl group having 1 carbonatom refers to HC(O)— (i.e. formyl), the acyl group having 2 carbonatoms refers to CH₃C(O)— (i.e. acetyl); propionyl, butyryl or valeryl.

In the present invention, unless otherwise specified, the followingterms in the description and the claims of the invention have thefollowing meanings:

The term “alkyl” refers to a saturated linear or branched monovalenthydrocarbon group having one to twenty carbon atoms. Examples of alkylinclude, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl,2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl.

The term “alkenyl” refers to a linear, branched or cyclic non-aromatichydrocarbon group having a specified number of carbon atoms and at leastone carbon-carbon double bond. Alkenyl is preferably having onecarbon-carbon double bond, and up to four non-aromatic carbon-carbondouble bonds can be present. Thus, “C₂-12 alkenyl” refers to an alkenylgroup having 2 to 12 carbon atoms. “C₂-6 alkenyl” refers to an alkenylgroup having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl.

The term “aryl” (used alone or included in other groups) refers to anystable monocyclic or bicyclic carbon ring which can have up to 7 atomsin each ring, wherein at least one ring is aromatic. Examples of theabove aryl include phenyl, naphthyl, tetrahydronaphthyl,2,3-dihydroindenyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It isto be understood that when the aryl is a bicyclic substituent and one ofthe rings is non-aromatic, the linkage is through the aromatic ring.

The term “aromatic hetero group” or “heteroaryl” (used alone or includedin other groups) refers to a stable monocyclic ring or bicyclic ringwhich can have up to 7 atoms in each ring, and at least one of the ringsis an aromatic ring having 1 to 4 heteroatoms independently selectedfrom O, N and S. The heteroaryl defined herein includes but not limitedto acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl,benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl,quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidyl, pyrryl, tetrahydroquinoline. Asdefined in the “heterocycloalkyl”, “heteroaryl” can also be understoodto include the N-oxide derivative of any nitrogenous heteroaryl. Whenthe heteroaryl is a bicyclic substituent and one of the rings isnon-aromatic or without any heteroatom, it can be understood, thelinkage is through the aromatic ring or the heteroatom on the ring.

The term “halogen” includes F, Cl, Br, I.

The term “pharmaceutically acceptable salt” refers to a conventionalacid addition or a base addition salt which retains the biologicalactivity and the property of compound I and is formed from a suitablenon-toxic organic acid, inorganic acid, organic base or inorganic base.Examples of the acid addition salt include the salt derived from aninorganic acid and an organic acid, the inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,sulfamic acid, phosphorous acid, phosphorothioic acid, phosphoric acidand nitric acid, the organic acid such as formic acid, acetic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonicacid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid,tartaric acid, succinic acid, fumaric acid, mandelic acid, malic acid,camphorsulfonic acid, etc. Examples of the base addition salt includethe salt derived from ammonium, potassium, sodium, calcium, andquaternary ammonium hydroxide (e.g. tetramethylammonium hydroxide).Modification of a pharmaceutical compound (i.e. drug) into a salt inorder to obtain a compound with improved physical and chemicalstability, hygroscopicity, flowability, and solubility is a conventionalmethod well known to the pharmacists.

The “pharmaceutically acceptable” contained in the term“pharmaceutically acceptable carrier” refers to the compound ispharmaceutically acceptable and basically non-toxic when administered toa specific subject.

Without violating the common sense in the art, the above preferredconditions can be arbitrarily combined, then preferred embodiments ofthe present invention are obtained.

The reagents and raw materials used in the present invention arecommercially available.

The positive and progressive effect of the present invention is that thecompounds of the present invention exhibit a better inhibition rate ontumor cells.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the study of the effect of WYC-103 on the apoptosis oftumor-repopulating cells of B16-F1 melanoma.

FIG. 2 shows the study of the effect of WYC-209 on the apoptosis oftumor-repopulating cells of B16-F1 melanoma.

FIGS. 3a and 3b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of A549 lung cancer, wherein FIG. 3a showsthe inhibitory activity of WYC-209 on A549 lung cancer when beginningadministrating on the day 0; FIG. 3b shows the inhibitory activity ofWYC-209 on A549 lung cancer when beginning administrating on the 3rdday.

FIGS. 4a and 4b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of MCF-7 breast cancer, wherein FIG. 4ashows the inhibitory activity of WYC-209 on MCF-7 breast cancer whenbeginning administrating on the day 0; FIG. 4b shows the inhibitoryactivity of WYC-209 on MCF-7 breast cancer when beginning administratingon the 3rd day.

FIGS. 5a and 5b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of MDA-MB-435S melanoma, wherein FIG. 5ashows the inhibitory activity of WYC-209 on MDA-MB-435S melanoma whenbeginning administrating on the day 0; FIG. 5b shows the inhibitoryactivity of WYC-209 on MDA-MB-435S melanoma when beginningadministrating on the 3rd day.

FIGS. 6a and 6b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of A2780 ovarian cancer, wherein FIG. 6ashows the inhibitory activity of WYC-209 on A2780 ovarian cancer whenbeginning administrating on the day 0; FIG. 6b shows the inhibitoryactivity of WYC-209 on A2780 ovarian cancer when beginningadministrating on the 3rd day.

FIGS. 7a and 7b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of Hs-746T gastric cancer, wherein FIG. 7ashows the inhibitory activity of WYC-209 on Hs-746T gastric cancer whenbeginning administrating on the day 0; FIG. 7b shows the inhibitoryactivity of WYC-209 on Hs-746T gastric cancer when beginningadministrating on the 3rd day.

FIGS. 8a and 8b show the study of the inhibitory activity of WYC-209 onthe tumor-repopulating cells of MDA-MB-231 breast cancer, wherein FIG.8a shows the inhibitory activity of WYC-209 on MDA-MB-231 breast cancerwhen beginning administrating on the day 0; FIG. 8b shows the inhibitoryactivity of WYC-209 on MDA-MB-231 breast cancer when beginningadministrating on the 3rd day.

FIGS. 9a and 9b show the study of the inhibitory activity ofWYC-331 onthe tumor-repopulating cells of A2780 ovarian cancer and MDA-MB-231breast cancer, wherein FIG. 9a shows the inhibitory activity ofWYC-331on A2780 ovarian cancer when beginning administrating on the 3rd day;FIG. 9b shows the inhibitory activity of WYC-331 on MDA-MB-231 breastcancer when beginning administrating on the 3rd day.

FIGS. 10a and 10b show the study of the toxicity of WYC-209 (WYC-209inhibits the proliferation of B16 cells, but has no significant effecton 3T3 cells); wherein, FIG. 10a shows treating 3T3 cells with 10 μMWYC-209 for 18 hours; FIG. 10b shows treating B16 cells with no WYC-209or 10 μM WYC-209 for 48 hours.

FIGS. 11a and 11b show the study of the toxicity of WYC-331; wherein,FIG. 11a shows treating 3T3 cells with 1 μM or 10 μM WYC-331 for 24hours; FIG. 11b shows treating B16 cells with 1 μM or 10 μM WYC-331 for24 hours.

FIG. 12 shows the tumor volume on the 19th day of the experiment in thestudy of the inhibitory activity of WYC-103 on subcutaneous melanoma.

FIG. 13 shows the study of the body weight of mice and in vivo toxicityof WYC-103 on subcutaneous melanoma.

FIG. 14 shows the tumor volume on the 26th day of the experiment in thestudy of the inhibitory activity of WYC-103 on subcutaneous melanoma.

FIGS. 15a, 15b, 15c, 15d, 15e and 15f show the study of the inhibitoryactivity of WYC-103 on metastatic melanoma in the lung; wherein, FIG.15a shows the lung tissue on the 29th day of the experiment whereinjecting 3000 tumor-repopulating cells of melanoma and administratingWYC-103; FIG. 15b shows the lung tissue on the 29th day of theexperiment where injecting 3000 tumor-repopulating cells of melanoma andadministrating DMSO; FIG. 15c shows the lung tissue on the 35th day ofthe experiment where injecting 3000 tumor-repopulating cells of melanomaand administrating WYC-103; FIG. 15d shows the lung tissue on the 35thday of the experiment where injecting 3000 tumor-repopulating cells ofmelanoma and administrating DMSO; FIG. 15e shows the lung tissue on the37th day of the experiment where administrating WYC-103; FIG. 15f showsthe lung tissue on the 37th day of the experiment where administratingDMSO.

FIGS. 16a, 16b and 16c show the study of the inhibitory activity ofWYC-209 on metastatic melanoma in the lung, wherein, FIG. 16a shows thelung tissue in the experiment where administrating DMSO; FIG. 16b showsthe lung tissue in the experiment where administrating 1.0M WYC-209;FIG. 16c shows the lung tissue in the experiment where administrating 1μM WYC-209.

FIG. 17 shows the single crystal structure of WYC-209A.

FIG. 18 shows the single crystal structure of WYC-209B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following embodiments further illustrate the present invention, butthe present invention is not limited thereto. The experimental methodsthat do not specify the specific conditions in the following embodimentsare selected according to conventional methods and conditions, oraccording to the description of the product.

Embodiment 1: methyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate

Commercially available 6-ethynyl-4,4-dimethylthiochroman (202.8 mg, 1mmol) and methyl 2-hydroxy-4-iodobenzoate (292.1 mg, 1 mmol) used as rawmaterial were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (14mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dryiPr₂NH were added via syringe. The reaction was continued at roomtemperature for 8 h and monitored by TLC. After completion of thereaction, the reaction was quenched with saturated ammonium chloridesolution, and the mixture was diluted with ethyl acetate, washed withsaturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=100:1 to 20:1) to give WYC-101 (296 mg, 81%). ¹H NMR (400 MHz,CDCl₃) δ 7.79 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.12 (d, 1H),7.06-7.07 (d, 1H), 7.00-7.02 (dd, 1H), 3.95 (s, 3H), 3.03-3.06 (m, 2H),1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 170.09,161.38, 161.12, 153.37, 142.25, 134.10, 130.91, 130.00, 129.85, 129.24,126.73, 122.45, 120.25, 117.90, 111.95, 93.23, 88.03, 77.48, 77.16,76.84, 52.52, 37.27, 32.54, 29.99, 23.43; ESI(+)-MS: 353.3 [M+1]⁺.

Embodiment 2: methyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate

6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl2-methoxy-4-iodobenzoate (292 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (7.6 mg,0.04 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.2 mL dry iPr₂NH were added via syringe. Thereaction was continued at room temperature for 8 h and monitored by TLC.After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution, and the mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-102 (300 mg,82%). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, 1H), 7.53 (d, 1H), 7.18-7.20(dd, 1H), 7.11-7.13 (dd, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 3.98 (s, 3H),3.89 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³CNMR (101 MHz, CDCl₃) δ 166.25, 159.05, 142.07, 133.98, 133.58, 131.89,129.90, 129.13, 128.85, 126.70, 123.39, 119.42, 117.88, 114.84, 92.50,88.07, 77.48, 77.16, 76.84, 56.18, 52.18, 37.23, 33.06, 30.06, 23.31;ESI(+)-MS: 367.4 [M+1]⁺.

Embodiment 3: ethyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate

6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and ethyl2-hydroxy-4-iodobenzoate (292 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (7.6 mg,0.04 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.2 mL dry iPr₂NH were added via syringe. Thereaction was continued at room temperature for 8 h and monitored by TLC.After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution, and the mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-103 (300 mg,82%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, 1H), 7.52 (s, 1H), 7.18-7.20(d, 1H), 7.12 (s, 1H), 7.06-7.07 (s, 1H), 7.00-7.02 (s, 1H), 4.39-4.44(q, 2H), 3.04-3.06 (t, 2H), 1.95-1.97 (t, 2H), 1.44 (t, 3H), 1.35 (s,6H); ¹³C NMR (101 MHz, CDCl₃) δ 169.97, 161.45, 142.27, 134.07, 130.80,130.02, 129.91, 129.26, 126.74, 122.37, 120.25, 117.94, 112.22, 93.19,88.02, 77.48, 77.36, 77.16, 76.84, 61.71, 37.30, 33.12, 30.11, 29.85,23.37, 14.34; ESI(+)-MS: 367.5 [M+1].

Embodiment 4: ethyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate

6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and ethyl2-methoxy-4-iodobenzoate (306 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (7.6 mg,0.04 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.2 mL dry iPr₂NH were added via syringe. Thereaction was continued at room temperature for 8 h and monitored by TLC.After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution, and the mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-104 (293 mg,77%). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=7.9 Hz, 1H), 7.53 (d, J=1.7Hz, 1H), 7.20 (dd, J=8.2, 1.7 Hz, 1H), 7.14-7.11 (m, 1H), 7.11-7.05 (m,2H), 4.36 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.07-3.04 (m, 2H), 1.95-1.98(m, 2H), 1.39 (t, 3H), 1.35 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 165.81,159.12, 142.28, 133.97, 131.77, 129.96, 129.19, 128.70, 126.76, 123.42,119.93, 117.98, 114.94, 92.39, 77.48, 77.37, 77.16, 76.85, 61.07, 56.25,37.31, 33.13, 30.14, 29.85, 23.37, 14.46; ESI(+)-MS: 381.4 [M+1]⁺.

Embodiment 5: 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoicacid

WYC-103 (183 mg, 0.5 mmol) was dissolved in 5 mL THF, then 1 mL 0.5MNaOH solution was added dropwise. The reaction was continued at roomtemperature for 8 hours and monitored by TLC. After completion of thereaction, the reaction solution was neutralized to pH 7 with 0.5M HClsolution, diluted with ethyl acetate, washed with saturated ammoniumchloride solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=10:1 to 1:1) togive WYC-105 (144 mg, 85%). ¹H NMR (500 MHz, cdcl₃) δ 10.50 (s, 1H),7.86-7.84 (d, 1H), 7.53 (d, 1H), 7.21-7.19 (dd, 1H), 7.14 (d, 1H),7.08-7.06 (d, 1H), 7.05-7.04 (dd, 1H), 3.07-3.04 (m, 1H), 1.98-1.95 (m,1H), 1.35 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 171.84, 161.46, 142.17,131.83, 130.58, 129.91, 129.16, 126.63, 120.24, 117.56, 110.03, 89.85,37.15, 32.99, 29.97, 29.70, 23.24; ESI(−)-MS: 337.1 [M−1]⁻.

Embodiment 6: methyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate

WYC-104 (190 mg, 0.5 mmol) was dissolved in 5 mL THF, then 1 mL 0.5MNaOH solution was added dropwise. The reaction was continued at roomtemperature for 8 hours and monitored by TLC. After completion of thereaction, the reaction solution was neutralized to pH 7 with 0.5M HClsolution, diluted with ethyl acetate, washed with saturated ammoniumchloride solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=10:1 to 4:1) togive WYC-106 (151 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ 10.60 (s, 1H),8.14 (d, J=7.9 Hz, 1H), 7.54 (s, 1H), 7.28 (m, 2H), 7.22 (m, 1H), 7.08(d, J=7.9 Hz, 1H), 4.12 (s, 3H), 3.06 (m, 2H), 1.96 (m, 2H), 1.35 (s,6H); ¹³C NMR (101 MHz, CDCl₃) δ 165.02, 157.85, 142.36, 134.56, 133.90,130.59, 130.00, 129.21, 126.81, 125.42, 117.51, 116.99, 114.42, 94.06,87.56, 77.48, 77.36, 77.16, 76.84, 56.98, 37.22, 33.12, 30.10, 29.83,23.37; ESI(−)-MS: 351.2 [M−1]⁻.

Embodiment 7: methyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-hydroxybenzoate

6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl3-hydroxy-4-iodobenzoate (278.1 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (7.6 mg,0.04 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.2 mL dry iPr₂NH were added via syringe. Thereaction was continued at room temperature for 8 h and monitored by TLC.After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution, and the mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=100:1 to 10:1) to give WYC-107 (245 mg,71%). ¹H NMR (500 MHz, CDCl₃) δ 7.64 (d, J=1.5 Hz, 1H), 7.58 (dd, J=8.0,1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.19 (dd,J=8.2, 1.7 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.02 (s, 1H), 3.91 (s, 3H),3.06-3.04 (m, 2H), 1.94-1.97 (m, 2H), 1.34 (s, 6H); ¹³C NMR (101 MHz,CDCl₃) δ 166.45, 156.21, 142.31, 134.62, 131.53, 131.43, 129.70, 128.97,126.73, 121.48, 117.03, 115.72, 114.61, 99.27, 81.86, 77.37, 77.05,76.74, 52.33, 37.06, 32.99, 29.94, 23.24; ESI(+)-MS: 353.4 [M+1]⁺.

Embodiment 8: methyl4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-methoxybenzoate

6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl3-methoxy-4-iodobenzoate (292.1 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (7.6 mg,0.04 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.2 mL dry iPr₂NH were added via syringe. Thereaction was continued at room temperature for 8 h and monitored by TLC.After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution, and the mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=100:1 to 10:1) to give WYC-108 (275 mg,75%). ¹H NMR (500 MHz, CDCl₃) δ 7.61-7.63 (d, 1H), 7.52-7.56 (m, 3H),7.21-7.23 (dd, 1H), 7.05-7.07 (d, 1H), 3.97 (s, 3H), 3.93 (s, 3H),3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); ¹³C NMR (126 MHz,cdcl₃) δ 166.59, 159.56, 141.99, 133.50, 133.19, 130.64, 129.80, 129.14,126.49, 121.75, 118.27, 111.25, 96.82, 84.38, 77.26, 77.01, 76.76,56.07, 52.29, 37.24, 32.97, 29.98, 23.22; ESI(+)-MS: 367.3 [M+1]+.

Embodiment 9: 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-methoxybenzoicacid

WYC-108 (190 mg, 0.5 mmol) was dissolved in 5 mL THF, and 1 mL 0.5M NaOHsolution was added dropwise. The reaction was continued at roomtemperature for 8 hours and monitored by TLC. After completion of thereaction, the reaction solution was neutralized to pH 7 with 0.5M HClsolution, diluted with ethyl acetate, washed with saturated ammoniumchloride solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=10:1 to 2:1) togive WYC-110 (1541 mg, 80%). ¹H NMR (500 MHz, CDCl₃) δ 7.69 (dd, 1H),7.61 (s, 1H), 7.58-7.55 (m, 2H), 7.23 (dd, 1H), 7.07 (d, 1H), 3.99 (s,3H), 3.06-3.04 (m, 2H), 1.97-1.95 (m, 2H), 1.34 (s, 6H); ESI(+)-MS:339.3 [M+1]+.

Embodiment 10:2-cyano-5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidine

Commercially available 4,4-dimethyl-6-ethynylthiochroman (202.8 mg, 1.0mmol) and 2-cyano-5-chloropyrimidine (93 mg, 0.67 mmol) used as rawmaterial were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (23mg, 0.03 mmol) and CuI (19 mg, 0.1 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 2 mL dry DMF and 0.25 mL dryEt3N were added via syringe. The reaction was continued at 50° C. for 22h and monitored by TLC. After completion of the reaction, the reactionsolution was cooled to room temperature and the reaction was quenchedwith saturated ammonium chloride solution. The mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=30:1) to give WYC-202 (133 mg, 65%). ¹HNMR (400 MHz, CDCl₃) δ 8.89 (s, 2H), 7.55 (d, J=1.6 Hz, 1H), 7.21 (dd,J=8.2, 1.7 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 3.11-3.03 (m, 2H), 2.01-1.93(m, 2H), 1.35 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 159.21, 142.59,141.79, 136.33, 130.15, 129.31, 126.98, 122.88, 116.13, 115.70, 101.85,81.24, 37.02, 33.15, 30.02, 23.42. ESI(+)-MS: 306.3 [M+1]⁺.

Embodiment 11: ethyl2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate

4,4-Dimethyl-6-ethynylthiochroman (202.8 mg, 1.0 mmol) and ethyl2-chloropyrimidin-5-carboxylate (156 mg, 0.83 mmol) used as raw materialwere added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (42 mg, 0.06mmol) and CuI (19 mg, 0.1 mmol). After the flask was purged with argonfor 3 times to remove oxygen, 2 mL dry DMF and 0.3 mL dry Et3N wereadded via syringe. The reaction was continued at 80° C. for 22 h andmonitored by TLC. After completion of the reaction, the reactionsolution was cooled to room temperature and the reaction was quenchedwith saturated ammonium chloride solution. The mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=15:1) to give WYC-203 (257 mg, 73%). ¹HNMR (500 MHz, CDCl₃) δ 9.24 (s, 2H), 7.69 (d, J=1.7 Hz, 1H), 7.33 (dd,J=8.2, 1.8 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.45 (q, J=7.1 Hz, 1H),3.11-2.99 (m, 2H), 1.99-1.92 (m, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.33 (s,6H); ¹³C NMR (126 MHz, CDCl₃) δ 163.52, 158.44, 155.85, 142.39, 136.48,131.36, 130.15, 126.83, 121.88, 115.96, 92.65, 87.97, 62.14, 37.09,33.14, 30.05, 23.43, 14.38. ESI(+)-MS: 353.2 [M+1]⁺.

Embodiment 12: methyl5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate

WYC-202 (50 mg, 0.164 mmol) was added to a flask, followed by additionof a solution of NaOH (20 mg, 0.491 mmol) in 0.5 mL water and 0.5 mLmethanol. Then the reaction was continued at 60° C. for 5 h andmonitored by TLC. After completion of the reaction, the reactionsolution was neutralized to pH 7 with 1M HCl solution, diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=15:1) to give WYC-204 (39 mg, 74%). ¹HNMR (500 MHz, CDCl₃) δ 8.63 (s, 2H), 7.51 (d, J=0.7 Hz, 1H), 7.17 (dd,J=8.1, 0.9 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.04 (s, 3H), 3.11-2.91 (m,2H), 2.04-1.90 (m, 2H), 1.34 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 164.02,161.24, 142.32, 134.10, 129.72, 128.97, 126.77, 117.65, 113.33, 94.71,81.81, 55.37, 37.28, 33.12, 30.11, 23.36. ESI(+)-MS: 339.2 [M+1]+.

Embodiment 13: ethyl5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate

WYC-202 (50 mg, 0.164 mmol) was added to a flask, followed by additionof sodium ethoxide (34 mg, 0.492 mmol) and 5 mL ethanol. Then thereaction was continued at 45° C. overnight and monitored by TLC. Aftercompletion of the reaction, the reaction solution was neutralized toneutral with acid resin and filtered, the filtrate was diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=8:1) to give WYC-205 (36 mg, 62%). ¹HNMR (500 MHz, CDCl₃) δ 8.62 (s, 2H), 7.51 (s, 1H), 7.17 (dd, J=8.1, 0.8Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.09-3.00 (m,2H), 2.00-1.92 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.34 (s, 6H); ¹³C NMR(126 MHz, CDCl₃) δ 163.61, 161.23, 142.32, 134.05, 129.72, 128.97,126.77, 117.71, 113.13, 94.60, 81.91, 64.11, 37.30, 33.13, 30.11, 23.36,14.55. ESI(+)-MS: 353.5 [M+1]⁺.

Embodiment 14:2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-5-carboxylic acid

WYC-203 (50 mg, 0.142 mmol) was added to a flask, followed by additionof 2 mL 2.0 mol/L NaOH solution and 2 mL methanol. Then the reaction wascontinued at 45° C. for 5 h and monitored by TLC. After completion ofthe reaction, the reaction solution was neutralized to weak acidic with1 mol/L HCl solution, diluted with ethyl acetate, extracted, washed withsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (dichloromethane:methanol=15:1) to give WYC-206(41 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ 9.21 (s, 2H), 7.71 (d, J=1.6 Hz,1H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 3.14-3.06 (m,2H), 2.05-1.92 (m, 2H), 1.36 (s, 6H); ¹³C NMR (101 MHz, CD₃OD) δ 167.13,159.54, 155.24, 143.92, 137.92, 131.86, 130.67, 127.84, 117.11, 111.42,92.11, 88.26, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 38.12,33.99, 30.18, 23.98. ESI(+)-MS: 325.3 [M+1]⁺.

Embodiment 15:2-cyano-5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidine

WYC-202 (30 mg, 0.098 mmol) was added to a flask, followed by additionof 2 mL dry dichloromethane. After the mixture was cooled to 0° C. underan ice bath, mCPBA (24 mg, 0.098 mmol) was added. Then the reaction wascontinued for 1 hour under an ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-207 (27 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ8.95 (s, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.55 (dd,J=8.0, 1.5 Hz, 1H), 3.30-3.08 (m, 2H), 2.44 (ddd, J=15.0, 10.1, 2.0 Hz,1H), 1.93 (ddd, J=15.1, 9.2, 2.1 Hz, 1H), 1.49 (s, 3H), 1.36 (s, 3H);¹³C NMR (126 MHz, CDCl₃) δ 159.64, 145.41, 142.59, 131.57, 130.38,130.36, 124.24, 121.99, 115.52, 99.38, 83.14, 43.53, 34.76, 31.38,31.31, 29.96. ESI(+)-MS: 322.3 [M+1]⁺.

Embodiment 16: ethyl5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate

WYC-205 (70 mg, 0.2 mmol) was added to a flask, followed by addition of3 mL dry dichloromethane. After the mixture was cooled to 0° C. under anice bath, mCPBA (49 mg, 0.2 mmol) was added. Then the reaction wascontinued for 1 hour under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-208 (68 mg, 93%). ¹H NMR (500 MHz, CDCl₃) δ8.66 (s, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=7.7 Hz,1H), 4.47 (q, J=7.1 Hz, 2H), 3.16 (dt, J=20.8, 11.7 Hz, 2H), 2.46 (dd,J=14.5, 10.3 Hz, 1H), 1.90 (dd, J=14.6, 8.0 Hz, 2H), 1.48 (s, 3H), 1.45(t, J=7.1 Hz, 3H), 1.34 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.95,161.56, 145.06, 131.11, 130.39, 129.99, 125.91, 112.28, 93.14, 84.74,64.30, 43.37, 34.61, 31.36, 31.23, 29.76, 14.52. ESI(+)-MS: 369.4[M+1]⁺.

Embodiment 17: ethyl2-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate

WYC-203 (48 mg, 0.14 mmol) was added to a flask, followed by addition of3 mL dry dichloromethane. After the mixture was cooled to 0° C. under anice bath, mCPBA (34 mg, 0.14 mmol) was added. Then the reaction wascontinued for 1 hour under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-209 (43 mg, 84%). ¹H NMR (500 MHz, CDCl₃) δ9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 4.47 (q, J=7.1Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15-3.07 (m, 1H), 2.43 (dd, J=14.0,10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t,J=7.2 Hz, 3H), 1.34 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.33, 158.54,155.32, 145.19, 132.61, 131.06, 130.22, 124.22, 122.62, 89.60, 89.35,62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI(+)-MS: 369.4 [M+1]+;HRMS-ESI (m/z) calculated C₂₀H₂₁N₂O₃S, 369.1273 [M+1]⁺, found 369.1267.

WYC-209A: ethyl2-((4,4-dimethyl-1S-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate

Diethyl D-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH₂Cl₂(1 mL), and Ti(iso-PrO)₄ (0.2 mmol, 58 μL) was quickly added at 16° C.After the mixture was stirred for 3 minutes, water (3.6 μL, 0.2 mmol)was slowly added dropwise, and the mixture was stirred for another 20minutes. The mixture was cooled to −20° C., then WYC-203 (69 mg, 0.2mmol) and cumene hydroperoxide (74 μL, 0.4 mmol) were quickly added, andthe reaction was stopped after 3 hours. The reaction solution was pouredinto 10 mL mixed solution of ferrous sulfate (0.2 g) and citric acid (67mg) in water, dioxane and diethyl ether (2:1:2), and the mixture wasstirred for 15 minutes. The aqueous phase was extracted with diethylether, the organic layers were combined, washed with 0.5M K₂CO₃ andsaturated sodium chloride solution, dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-209A (43 mg, 84%, ee %=90%). The product wasrecrystallized with diethyl ether to give WYC-209A (25 mg, ee %=99%). ¹HNMR (500 MHz, CDCl₃) δ 9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15-3.07 (m,1H), 2.43 (dd, J=14.0, 10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47(s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.34 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22,122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39.ESI(+)-MS: 369.4 [M+1]⁺. ee % was determined by chiral HPLC as follows:Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1250*4.6 mm, mobile phase: acetonitrile/H₂O=80:20, 20° C., 0.7 mL/min;the retention time was 8.592 min.

WYC-209B: ethyl2-((4,4-dimethyl-1R-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate

Diethyl L-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH₂Cl₂(1 mL), and Ti(iso-PrO)₄ (0.2 mmol, 58 μL) was quickly added at 16° C.After the mixture was stirred for 3 minutes, water (3.6 μL, 0.2 mmol)was slowly added dropwise and the mixture was stirred for another 20minutes. The mixture was cooled to −20° C., then WYC-203 (69 mg, 0.2mmol) and cumene hydroperoxide (74 μL, 0.4 mmol) were quickly added, andthe reaction was stopped after 3 hours. The reaction solution was pouredinto 10 mL mixed solution of ferrous sulfate (0.2 g) and citric acid (67mg) in water, dioxane and diethyl ether (2:1:2), and the mixture wasstirred for 15 minutes. The aqueous phase was extracted with diethylether, the organic layers were combined, washed with 0.5M K₂CO₃ andsaturated sodium chloride solution, dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-209B (43 mg, 84%, ee %=90%). The product wasrecrystallized with diethyl ether to give WYC-209B (25 mg, ee %=99%). ¹HNMR (500 MHz, CDCl₃) δ 9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15-3.07 (m,1H), 2.43 (dd, J=14.0, 10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47(s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.34 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22,122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39.ESI(+)-MS: 369.4 [M+1]⁺. ee % was determined by chiral HPLC as follows:Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1250*4.6 mm, mobile phase: acetonitrile/H₂O=80:20, 20° C., 0.7 mL/min;the retention time was 9.147 min.

The single crystal structure diagrams of WYC-209A and WYC-209B wereshown in FIG. 17 and FIG. 18 respectively. The crystal belonged tomonoclinic crystal system, the space group was P21, and the unit cellparameters were as follows: a=7.9718(11) Å, b=22.980(3) Å, c=10.4356(15Å, α=90°, β=103.010(3)°, γ=90°, the unit cell volume was 1862.7(5) Å3,the asymmetric unit number in unit cell Z=4, the density was 1.314Mg/m3.

TABLE 1 Atomic coordinates (×10⁴) and isotropic displacement parameters(Å² × 10³) x y z U(eq) S(1) −4896(2)  5378(1) 9438(2) 64(1) S(2)9768(2)  9738(1) 5287(2) 60(1) N(1) 1166(9)  7867(3) 5358(7) 68(2) N(2)3322(10) 7134(3) 5625(7) 70(2) N(3) 1503(9)  8087(3) 9298(6) 60(2) N(4)3711(8)  7376(3) 9624(7) 63(2) O(1) −5859(9)  5779(3) 10024(8)  114(3) O(2) 3797(11) 8790(3) 3055(8) 115(3)  O(3) 5939(11) 8134(4) 3481(9)131(3)  O(4) 11314(7)  9798(4) 6315(6) 115(3)  O(5) 1038(10) 6474(3)11962(9)  121(3)  O(6) −1155(8)  7052(3) 11353(7)  97(2) C(1) −3530(11) 4926(3) 10594(7)  65(2) C(2) −2367(10)  4602(3) 9909(7) 64(2) C(3)−944(9)  4969(3) 9545(6) 48(2) C(4) −1618(8)  5549(3) 8933(5) 39(1) C(5)−3243(8)  5771(3) 8896(6) 40(1) C(6) −3757(9)  6307(3) 8344(6) 50(2)C(7) −2673(9)  6630(3) 7800(6) 50(2) C(8) −1059(9)  6425(3) 7787(6)46(2) C(9) −526(9)  5892(3) 8371(6) 46(2) C(10)  60(10) 6751(3) 7154(7)53(2) C(11)  913(11) 7023(3) 6582(7) 59(2) C(12) 1867(9)  7364(3)5806(6) 48(2) C(13) 2019(10) 8163(3) 4650(8) 62(2) C(14) 3524(10)7974(3) 4364(7) 56(2) C(15) 4120(12) 7454(3) 4910(9) 70(2) C(16)4393(13) 8342(4) 3535(9) 74(2) C(17) 7143(16) 8549(6)  2894(10) 109(4) C(18) 6503(17) 8410(6)  1579(12) 131(5)  C(19)  510(11) 5085(4)10778(7)  74(2) C(20) −240(12) 4602(4) 8538(9) 74(2) C(21) 8964(12)10485(4)   5260(10) 55(2) C(22) 7109(12) 10483(5)   4503(10) 52(2) C(23)5908(9)  10236(3)  5340(7) 50(2) C(24) 6529(7)  9648(3) 5968(5) 37(1)C(25) 8142(8)  9413(3) 6009(6) 42(2) C(26) 8650(9)  8878(3) 6594(7)55(2) C(27) 7552(10) 8576(3) 7197(7) 57(2) C(28) 5936(8)  8802(3)7184(6) 41(1) C(29) 5458(8)  9327(3) 6566(6) 41(1) C(30) 4800(10)8488(3) 7839(6) 51(2) C(31) 3955(10) 8211(3) 8418(7) 52(2) C(32)2989(9)  7879(3) 9141(6) 48(2) C(33) 2812(10) 7071(3) 10342(8)  63(2)C(34) 1310(9)  7251(3) 10593(7)  49(2) C(35)  662(11) 7776(3) 10023(8) 62(2) C(36)  405(11) 6883(4) 11401(8)  66(2) C(37) −2274(14)  6657(6)12000(11) 107(4)  C(38) −1890(19)  6799(6) 13361(13) 130(5)  C(39)4275(12) 10156(4)  4320(7) 72(2) C(40) 5551(13) 10640(4)  6396(8) 74(2)

Embodiment 18:2-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylicacid

WYC-206 (34 mg, 0.105 mmol) was added to a flask, followed by additionof 1.5 mL dry dichloromethane. After the mixture was cooled to 0° C.under an ice bath, mCPBA (26 mg, 0.105 mmol) was added. Then thereaction was continued for 1 hour under the ice bath and another 2 h atroom temperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(DCM:MeOH=12:1) to give WYC-210 (23 mg, 68%). ¹H NMR (500 MHz, pyridine)δ 9.66 (s, 2H), 7.99-7.85 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 3.20 (t,J=10.7 Hz, 1H), 3.14-3.02 (m, 1H), 2.32 (dd, J=12.9, 10.4 Hz, 1H), 1.72(dd, J=13.2, 9.4 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H). ¹³C NMR (126 MHz,pyridine) δ 166.30, 159.03, 155.15, 145.73, 142.20, 132.56, 130.90,130.31, 125.00, 124.29, 90.65, 88.52, 43.70, 34.73, 30.89, 30.62, 29.97.ESI(+)-MS: 341.1 [M+1]⁺.

Embodiment 19: 2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoicacid

6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and2-amino-4-iodobenzoic acid (263 mg, 1 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) and CuI (23 mg,0.12 mmol). After the flask was purged with argon for 3 times to removeoxygen, 10 mL dry DMF and 0.2 mL dry Et3N were added via syringe. Thenthe reaction was continued at 75° C. for 12 h and monitored by TLC.After completion of the reaction, the reaction solution was cooled toroom temperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=5:1) to give WYC-212 (286 mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ7.88 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.1, 1.8 Hz,1H), 7.06 (d, J=8.1 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H), 6.81 (dd, J=8.3,1.5 Hz, 1H), 3.08-3.02 (m, 3H), 1.99-1.94 (m, 2H), 1.35 (s, 6H); ¹³C NMR(126 MHz, CDCl₃) δ 165.25, 165.23, 163.21, 161.20, 142.29, 134.42,133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12,117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62,37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)-MS: 338.3 [M+1]⁺.

Embodiment 20:2-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic acid

WYC-212 (200 mg, 0.3 mmol) was added to a flask, followed by addition of10 mg DMAP, then 5 mL dry pyridine was added under argon atmosphere. Themixture was cooled to 0° C. under an ice bath, and 43 μL acetyl chloridewas added dropwise. The reaction was continued for 10 min under the icebath and another 5h at room temperature, meanwhile TLC was used tomonitor the reaction. After completion of the reaction, the reaction wasquenched with methanol. The mixture was diluted with ethyl acetate,washed with 1 mol/L hydrochloric acid to remove pyridine, then washedwith saturated sodium chloride solution. The organic phase was driedover anhydrous sodium sulfate, filtered, concentrated and purified byflash column chromatography (PE:EtOAc=20:1) to give WYC-213 (195 mg,87%). ¹H NMR (500 MHz, CDCl₃) δ 8.13 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.3Hz, 1H), 7.58 (dd, J=8.1, 1.5 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.21 (dd,J=8.1, 1.8 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.09-3.03 (m, 2H), 2.47 (s,3H), 1.99-1.92 (m, 2H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 160.95,159.37, 146.56, 142.37, 134.76, 132.31, 131.05, 130.06, 129.32, 128.95,128.49, 126.82, 117.47, 115.64, 95.32, 87.52, 37.23, 33.13, 30.09,23.39, 21.54. ESI(+)-MS: 380.4 [M+1]⁺.

Embodiment 21: 6-ethynyl-4,4-dimethyl-1-oxothiochroman

6-Ethynyl-4,4-dimethylthiochroman (2.03 g, 10 mmol) was added to aflask, followed by addition of 27 mL dry dichloromethane. After themixture was cooled to 0° C. under an ice bath, mCPBA (1.73 g, 10 mmol)was added. Then the reaction was continued for 1 h under the ice bathand another 2 h at room temperature, meanwhile TLC was used to monitorthe reaction. After completion of the reaction, the reaction wasquenched with sodium thiosulfate solution, the mixture was diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=3:1) to give1-oxo-6-ethynyl-4,4-dimethylthiochroman (1.43 g, 72%). ¹H NMR (500 MHz,CDCl₃) δ 7.41 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=8.0 Hz, 1H),2.93-2.74 (m, 3H), 2.14 (ddd, J=14.6, 10.5, 1.7 Hz, 1H), 1.58 (ddd,J=15.0, 8.7, 1.8 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 144.82, 138.91, 131.70, 130.53, 130.17, 125.60, 82.69, 79.39,43.23, 34.47, 31.27, 31.13, 29.67. ESI(+)-MS: 219.3 [M+1]⁺.

Embodiment 22:2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoic acid

1-Oxo-6-ethynyl-4,4-dimethylthiochroman (263 mg, 1.0 mmol) and2-amino-4-iodobenzoic acid (262 mg, 1.2 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) and CuI (23 mg,0.12 mmol). After the flask was purged with argon for 3 times to removeoxygen, 4 mL dry DMF and 0.2 mL dry Et3N were added via syringe. Thenthe reaction was continued at 70° C. for 8 h and monitored by TLC. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=50:1) to give the product (275 mg, 78%). ¹H NMR (500 MHz,pyridine) δ 8.37 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (s,1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 5.67 (s, 1H),3.20-3.14 (m, 1H), 3.11-3.05 (m, 1H), 2.38 (ddd, J=14.2, 10.3, 1.7 Hz,1H), 1.74-1.68 (m, 1H), 1.26 (s, 3H), 1.17 (s, 3H); ¹³C NMR (126 MHz,pyridine) δ 171.06, 152.34, 145.52, 140.46, 132.80, 131.65, 130.43,130.20, 127.92, 126.32, 119.79, 118.58, 112.43, 91.82, 90.33, 55.01,43.59, 34.63, 30.93, 30.63, 29.80. ESI(+)-MS: 354.3 [M+1]⁺.

Embodiment 23: methyl2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-214 (150 mg, 0.425 mmol) was added to a flask, followed by additionof sodium carbonate (176 mg, 1.275 mmol), then 3 mL dry DMF andiodomethane (40 μL, 0.637 mmol) were added under argon atmosphere. Themixture was slowly heated to 100° C., then the reaction was continuedfor 6h and monitored by TLC. After completion of the reaction, thereaction solution was cooled to room temperature, diluted with ethylacetate, washed with saturated sodium bicarbonate solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=20:1) to give WYC-215 (143 mg, 92%). ¹H NMR(500 MHz, CDCl₃) δ 7.84 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.58(d, J=1.5 Hz, 1H), 7.48 (dd, J=8.0, 1.6 Hz, 1H), 6.87 (d, J=1.3 Hz, 1H),6.81 (dd, J=8.3, 1.5 Hz, 1H), 3.88 (s, 3H), 3.20 (ddd, J=12.9, 10.6, 2.2Hz, 1H), 3.10 (ddd, J=13.1, 8.7, 2.3 Hz, 1H), 2.46 (ddd, J=14.9, 10.5,2.2 Hz, 1H), 1.89 (ddd, J=15.1, 8.7, 2.2 Hz, 3H), 1.47 (s, 3H), 1.33 (s,3H); ¹³C NMR (126 MHz, CDCl₃) δ 168.19, 150.04, 144.92, 138.59, 131.48,131.30, 130.34, 130.18, 128.13, 126.44, 119.72, 119.64, 111.06, 90.93,90.26, 51.84, 43.28, 34.57, 31.36, 31.21, 29.73. ESI(+)-MS: 368.4[M+1]⁺.

Embodiment 24: ethyl2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

WYC-212 (50 mg, 0.15 mmol) was added to a flask, followed by addition of2 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to0° C. under an ice bath, then 0.15 mL concentrated sulfuric acid wasadded dropwise. After completion of the dropwise addition, the reactionsolution was heated to reflux and stirred for 4 h, meanwhile TLC wasused to monitor the reaction. After completion of the reaction, thereaction solution was cooled to room temperature, treated with 2 mol/Lsodium hydroxide to neutralize sulfuric acid to make a neutral solution,then washed with saturated sodium chloride solution. The organic phasewas dried over anhydrous sodium sulfate, filtered, dried, and purifiedby flash column chromatography (PE:EtOAc=10:1) to give WYC-216 (14 mg,25%). ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J=8.3 Hz, 1H), 7.51 (d, J=1.6Hz, 1H), 7.17 (dd, J=8.1, 1.7 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.83 (d,J=1.3 Hz, 1H), 6.79 (dd, J=8.3, 1.4 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H),3.06-3.03 (m, 2H), 1.97-1.94 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.34 (s,6H). ¹³C NMR (126 MHz, CDCl₃) δ 167.92, 150.10, 142.22, 133.72, 131.35,129.95, 129.19, 129.02, 126.70, 119.55, 119.39, 118.23, 110.80, 91.99,88.37, 60.61, 37.36, 33.12, 30.13, 23.37, 14.50. ESI(+)-MS: 366.4[M+1]+.

Embodiment 25: ethyl2-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

WYC-216 (80 mg, 0.22 mmol) was added to a flask, and 6 mg DMAP wasadded. The flask was purged with argon, then 2 mL dry pyridine wasadded. Then the mixture was cooled to 0° C. under an ice bath, andacetyl chloride (31 jL, 0.44 mmol) was added dropwise. The reaction wascontinued for 10 min under the ice bath and another 9h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with methanol. Themixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloricacid to remove pyridine, then washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=10:1) to give WYC-217 (71 mg,79%). ¹H NMR (500 MHz, CDCl₃) δ 11.12 (s, 1H), 8.88 (d, J=1.4 Hz, 1H),7.99 (d, J=8.3 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.20 (dd, J=3.6, 1.7 Hz,1H), 7.18 (dd, J=3.8, 1.7 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.38 (q,J=7.1 Hz, 2H), 3.06-3.03 (m, 2H), 2.24 (s, 3H), 1.97-1.94 (m, 2H), 1.42(t, J=7.1 Hz, 3H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 169.17,168.11, 142.25, 141.59, 133.98, 130.81, 130.17, 130.04, 129.24, 126.70,125.26, 122.97, 118.06, 114.16, 93.43, 88.37, 61.65, 37.36, 33.13,30.13, 25.68, 23.38, 14.34. ESI(+)-MS: 408.4 [M+1]+.

Embodiment 26: ethyl2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

Ethyl 2-amino-4-iodobenzoate (262.0 mg, 1.2 mmol) and1-oxo-6-ethynyl-4,4-dimethylthiochroman (263.0 mg, 1 mmol) were added toa flask, followed by addition of Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) and CuI(23 mg, 0.12 mmol). After the flask was purged with argon for 3 times toremove oxygen, 15 mL dry DMF and 0.2 mL dry Et3N were added via syringe.The reaction was continued at 75° C. for 12 h and monitored by TLC.After completion of the reaction, the reaction solution was cooled toroom temperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(DCM:MeOH=40:1) to give WYC-218 (275 mg, 78%). ¹H NMR (500 MHz,pyridine) δ 8.39 (d, J=8.1 Hz, 1H), 7.97-7.82 (m, 2H), 7.61 (s, 1H),7.38 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.25-3.01 (m, 2H), 2.40 (ddd,J=14.2, 10.3, 1.7 Hz, 1H), 1.73 (ddd, J=14.8, 8.8, 1.5 Hz, 1H), 1.28 (s,3H), 1.19 (s, 3H). ¹³C NMR (126 MHz, pyridine) 6171.75, 153.03, 150.76,150.74, 150.55, 150.53, 150.33, 150.31, 146.21, 141.15, 133.49, 132.34,131.12, 130.89, 128.61, 127.01, 120.48, 119.27, 113.12, 92.51, 91.02,44.28, 35.32, 31.62, 31.32, 30.49. ESI(+)-MS: 382.4 [M+1]+.

Embodiment 27: methyl2-methylamino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

WYC-212 (100 mg, 0.3 mmol) was added to a flask, followed by addition ofsodium carbonate (125 mg, 0.9 mmol). Then 3 mL dry DMF and iodomethane(281 μL, 0.445 mmol) were added under argon atmosphere, the reactionsolution was slowly heated to 100° C. and stirred for 4 h, meanwhile TLCwas used to monitor the reaction. After completion of the reaction, thereaction solution was cooled to room temperature, diluted with ethylacetate, washed with saturated sodium bicarbonate solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=20:1) to give WYC-219 (43 mg, 39%) and 3-69-2-2(45 mg, 43%). ¹H NMR (500 MHz, CDCl₃) δ 7.87 (d, J=8.2 Hz, 1H), 7.54 (s,1H), 7.20 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 6.78(d, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.08-3.02 (m, 2H), 2.95 (s, 3H),1.99-1.94 (m, 2H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 168.77,151.15, 142.24, 133.75, 131.64, 130.02, 129.68, 129.24, 126.71, 118.37,118.24, 114.31, 110.05, 92.11, 88.89, 51.79, 37.38, 33.14, 30.15, 23.39.ESI(+)-MS: 366.2 [M+1]⁺.

Embodiment 28: methyl2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

WYC-212 (100 mg, 0.3 mmol) was added to a flask, followed by addition ofpotassium carbonate (125 mg, 0.9 mmol). Dry DMF (3 mL) was added underdry argon atmosphere, and MeI (28 μL, 0.445 mmol) was added dropwise.The reaction was continued at 100° C. for 8 h. After completion of thereaction, the reaction solution was cooled to room temperature, dilutedwith ethyl acetate, successively washed with 1 moL/L HCl solution,saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=20:1) to give WYC-220 (45 mg, 44%). ¹H NMR (500 MHz, cdcl₃) δ7.83 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.1, 1.8 Hz,1H), 7.07 (d, J=8.1 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 6.81 (dd, J=8.3,1.5 Hz, 1H), 3.88 (s, 3H), 3.08-3.02 (m, 2H), 2.00-1.93 (m, 2H), 1.35(s, 6H). ¹³C NMR (126 MHz, cdcl₃) δ 168.25, 149.81, 142.19, 133.74,131.31, 129.92, 129.16, 129.15, 126.67, 119.74, 119.47, 118.15, 110.58,92.12, 88.28, 51.75, 37.32, 33.08, 30.09, 23.34. ESI(+)-MS: 352.4[M+1]⁻.

Embodiment 29:2-acetylamino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoicacid

WYC-214 (152 mg, 0.42 mmol) was added to a flask, followed by additionof 10 mg DMAP. 5 mL dry dichloromethane and 0.212 mL pyridine were addedunder argon atmosphere. After the reaction solution was cooled to 0° C.under an ice bath, acetyl chloride (67 μL, 0.84 mmol) was addeddropwise, and the reaction was continued for 10 min under the ice bathand another 12 h at room temperature, meanwhile TLC was used to monitorthe reaction. After completion of the reaction, the reaction wasquenched with methanol. The mixture was diluted with ethyl acetate,washed with 1 mol/L hydrochloric acid to remove pyridine, then washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:3) to give WYC-221 (147 mg, 89%). ¹H NMR (500 MHz, CDCl₃) δ8.12 (d, J=8.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.57 (dd, J=8.1, 1.5 Hz,1H), 7.54 (d, J=1.7 Hz, 1H), 7.21 (dd, J=8.1, 1.8 Hz, 1H), 7.08 (d,J=8.1 Hz, 1H), 3.07-3.03 (m, 2H), 2.46 (s, 3H), 1.99-1.94 (m, 2H), 1.35(s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 160.87, 159.36, 146.58, 142.34,134.73, 132.26, 131.01, 130.04, 129.30, 128.95, 128.45, 126.80, 117.45,115.64, 95.28, 87.51, 37.21, 33.11, 30.07, 23.38, 21.54. ESI(+)-MS:396.2 [M+1]+.

Embodiment 30: 2-(3-bromophenyl)acetaldehyde

2-(3-Bromophenyl)ethanol (676 μL, 5 mmol) was added to a flask, followedby addition of 10 mL dry dichloromethane, then DMP (2.5 g, 6 mmol) wasadded under an ice bath. The reaction was continued for 2 h under theice bath and another 0.5 h at room temperature, meanwhile TLC was usedto monitor the reaction. After completion of the reaction, the reactionsolution was cooled to 0° C. and the reaction was quenched with sodiumthiosulfate solution. The mixture was diluted with ethyl acetate andwashed with saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=15:1) to give2-(3-bromophenyl)acetaldehyde (0.86 g, 87%). ¹H NMR (300 MHz, CDCl₃) δ9.74 (1H, t, J=2.0), 7.46-7.37 (2H, m), 7.30-7.14 (2H, m), 3.67 (2H, d,J=2.0). ¹³C NMR (75 MHz, CDCl₃) δ 198.9, 134.5, 133.0, 131.0, 130.9,128.7, 123.3, 60.8. ESI(+)-MS: 199.1 [M+1]⁺.

Embodiment 31: ethyl 4-(3-bromophenyl)-2-butenoate

2-(3-bromophenyl)acetaldehyde (400 mg, 2.02 mmol) and Ph₃PCH═CO₂Et (703mg, 2.02 mmol) were added to a flask, followed by addition of 10 mL drytoluene under argon atmosphere. The reaction was continued at 900 for 8h and monitored by TLC. After completion of the reaction, the reactionsolution was cooled to 0° C., diluted with ethyl acetate, washed withsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=250:1) to give ethyl4-(3-bromophenyl)-2-butenoate (514 mg, 96%). E-configuration: ¹H NMR(500 MHz, CDCl₃) δ 7.36 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.17 (t, J=7.8Hz, 1H), 7.11-6.99 (m, 2H), 5.80 (dt, J=15.6, 1.6 Hz, 1H), 4.17 (q,J=7.1 Hz, 2H), 3.47 (dd, J=6.8, 1.0 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 166.29, 146.15, 140.06, 131.88, 130.29, 129.90,127.53, 123.02, 122.77, 77.41, 77.16, 76.91, 60.44, 38.00, 14.32.Z-configuration: ¹H NMR (500 MHz, CDCl₃) δ 7.38 (s, 1H), 7.36-7.33 (m,1H), 7.16 (dd, J=4.1, 1.4 Hz, 2H), 6.30 (dt, J=11.4, 7.6 Hz, 1H), 5.88(dt, J=11.4, 1.7 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.00 (dd, J=7.6, 1.4Hz, 2H), 1.31 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 166.33,146.76, 141.84, 131.76, 130.25, 129.60, 127.41, 122.74, 120.73, 60.23,34.73, 14.39.

Embodiment 32: ethyl 4-(3-bromophenyl)butanoate

Ethyl 4-(3-bromophenyl)-2-butenoate (1.05 g, 3.92 mmol) was added to aflask, followed by addition of (10% wt) dry Pd/C (220 mg, 0.194 mmol),then 20 mL ethyl acetate was added under argon atmosphere. After theflask was purged with hydrogen for 3 times, the reaction was continuedat room temperature under normal pressure for 24 h and monitored by TLC.After completion of the reaction, the reaction solution was filtered,concentrated and purified by flash column chromatography (PE:EtOAc=15:1)to give ethyl 4-(3-bromophenyl)butanoate (1.04 g, 98%). ¹H NMR (500 MHz,CDCl₃) δ 7.32 (dd, J=9.5, 1.3 Hz, 2H), 7.16-7.08 (m, 2H), 4.12 (q, J=7.1Hz, 2H), 2.64-2.59 (m, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.96-1.90 (m, 2H),1.25 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 173.27, 143.87,131.59, 130.01, 129.18, 127.22, 122.51, 60.40, 34.82, 33.57, 26.36,14.33. ESI(+)-MS: 271.2 [M+1]⁺.

Embodiment 33: 5-(3-bromophenyl)-2-methyl-2-pentanol

Ethyl 4-(3-bromophenyl)butanoate (0.53 g, 1.96 mmol) was added to aflask, followed by addition of 15 mL tetrahydrofuran under argonatmosphere. After the mixture was cooled to 0° C. under an ice bath,methylmagnesium bromide (2 mL, 5.89 mmol) was added dropwise. Thereaction was continued for 3 h at 0° C. and another 1 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to 0° C.and the reaction was quenched with ice water. The mixture was dilutedwith ethyl acetate, neutralized with 1 mol/L hydrochloric acid, washedwith saturated sodium carbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=15:1) to give 5-(3-bromophenyl)-2-methyl-2-pentanol (466 mg,93%). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 2H), 7.22-7.10 (m, 2H),2.62 (dt, J=15.0, 7.7 Hz, 2H), 1.76-1.64 (m, 2H), 1.56-1.47 (m, 2H),1.22 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 144.81, 131.40, 129.84, 128.81,127.05, 122.33, 70.73, 43.29, 35.95, 29.22, 26.00. ESI(+)-MS: 257.1[M+1].

Embodiment 34: 7-bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one

5-(3-Bromophenyl)-2-methyl-2-pentanol (340 mg, 1.33 mmol) was added to aflask, followed by addition of 2 mL dry dichloromethane under argonatmosphere. After the mixture was cooled to 0° C. under an ice bath, 0.2mL concentrated sulfuric acid was added dropwise, and the reaction wascontinued at room temperature for 4 h and monitored by TLC. Aftercompletion of the reaction, the reaction solution was diluted withwater, neutralized with 1 mol/L sodium hydroxide to neutralize sulfuricacid, diluted with ethyl acetate, washed with saturated sodium carbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered and evaporated to give 320mg white solid, which was added to a flask, followed by addition of 4.3mL. 71 mg chromium trioxide was dissolved in a mixed solution of 0.648mL acetic acid and 0.342 mL acetic anhydride, which was added to theflask under an ice bath. The reaction was continued for 2 h andmonitored by TLC. After completion of the reaction, the reactionsolution was diluted with EtOAc, washed three times with water, thenwashed with saturated sodium carbonate solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=10:1) to give7-bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one (268 mg, 80%). ¹H NMR(400 MHz, CDCl₃) δ 7.37 (dd, J=8.5, 1.6 Hz, 1H), 7.33-7.21 (m, 2H),2.24-2.05 (m, 2H), 1.87-1.77 (m, 1H), 1.58-1.49 (m, 1H), 1.35 (s, 3H),1.30 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 197.03, 151.09, 136.63, 132.77,130.15, 128.04, 120.57, 36.86, 35.04, 33.89, 29.65. ESI(+)-MS: 253.1[M+1]⁺.

Embodiment 35:7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol

7-Bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one (340 mg, 1.35 mmol)was added to a flask, followed by addition of 3 mL tetrahydrofuran underargon atmosphere. After the mixture was cooled to 0° C. under an icebath, phenylmagnesium bromide (2.7 mL, 2.7 mmol) was added dropwise. Thereaction was continued for 0.5 h at 0° C. and another 18 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to 0° C.and the reaction was quenched with ice water. The mixture was dilutedwith ethyl acetate, neutralized with 1 mol/L hydrochloric acid, washedwith saturated sodium carbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=100:1) to give7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol (280 mg,63%). ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.08 (m, 8H), 2.24-2.05 (m, 2H),1.87-1.77 (m, 1H), 1.58-1.49 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 148.11, 145.41, 143.32, 131.50, 131.18, 128.46,128.08, 127.15, 126.59, 119.96, 75.87, 37.69, 34.77, 34.09, 31.56,31.45. ESI(+)-MS: 331.1 [M+1]+.

Embodiment 36: 6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene

7-Bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (260 mg,0.79 mmol) was added to a flask, followed by additionofp-toluenesulfonic acid (27 mg, 0.16 mmol), then 2 mL dry toluene wasadded under argon atmosphere. The reaction was continued at 75° C. for0.5 h and monitored by TLC. After completion of the reaction, thereaction solution was cooled to room temperature and the reaction wasquenched with ice water. The mixture was diluted with ethyl acetate,washed with saturated sodium carbonate solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=250:1) to give6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (224 mg, 91%). ¹HNMR (500 MHz, CDCl₃) δ 7.44-7.40 (m, 2H), 7.39-7.33 (m, 4H), 7.24 (d,J=8.3 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.03 (t, J=4.7 Hz, 1H), 2.36 (d,J=4.7 Hz, 2H), 1.34 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 145.59, 144.16,140.35, 138.75, 136.15, 133.57, 131.80, 130.41, 128.72, 128.56, 127.87,127.46, 127.02, 125.79, 119.96, 63.05, 38.87, 33.65, 28.18. ESI(+)-MS:312.1 [M+1]⁺.

Embodiment 37:((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane

6-Bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (310 mg, 1.0 mmol)and trimethylethynylsilane (0.28 μL, 2 mmol) was added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (21 mg, 0.03 mmol) and CuI (11 mg,0.06 mmol). After the flask was purged with argon for 3 times to removeoxygen, 5 mL dry DMF and 0.2 mL dry Et₃N were added via syringe. Thereaction was continued at room temperature over night and monitored byTLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (petroleum ether) to give((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane(275 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.38 (m, 2H), 7.36-7.32(m, 4H), 7.28 (d, J=7.9 Hz, 10H), 7.11 (d, J=1.6 Hz, 1H), 5.97 (t, J=4.7Hz, 1H), 2.33 (d, J=4.7 Hz, 2H), 1.31 (s, 6H), 0.19 (s, 9H). ¹³C NMR(126 MHz, CDCl₃) δ 146.01, 140.79, 139.09, 133.98, 131.51, 129.25,128.83, 128.49, 127.29, 127.27, 123.92, 120.66, 105.45, 93.41, 38.88,33.90, 28.19, 0.16. ESI(+)-MS: 331.2 [M+1]⁺.

Embodiment 38: 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene

((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane(300 mg, 0.91 mmol) was added to a flask, followed by addition of TBAF(30 Mg, 0.115 mmol) and 2 mL dry tetrahydrofuran. The reaction wascontinued for 4 h and monitored by TLC. After completion of thereaction, the reaction solution was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EA=1000:1) to give6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (225 mg, 96.6%).¹H NMR (500 MHz, CDCl₃) δ 77.47-77.34 (m, 7H), 77.22 (d, J=1.6 Hz, 1H),76.04 (t, J=4.7 Hz, 1H), 72.98 (s, 1H), 72.39 (d, J=4.7 Hz, 2H), 71.38(s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 146.23, 140.58, 138.97, 134.13,131.41, 129.62, 128.77, 128.49, 127.34, 127.27, 124.04, 119.59, 83.98,76.59, 38.83, 33.85, 28.18. ESI(+)-MS: 259.2 [M+1]⁺.

Embodiment 39: methyl4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate

6-Ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (116 mg, 0.45mmol) and methyl 2-hydroxy-4-iodobenzoate (μL, 0.9 mmol) was added to aflask, followed by addition of Pd(PPh₃)₂Cl₂ (9.5 mg, 0.0135 mmol) andCuI (5.1 mg, 0.027 mmol). After the flask was purged with argon for 3times to remove oxygen, 3 mL dry DMF and 0.2 mL dry Et₃N were added viasyringe. The reaction was continued at room temperature for 8 h andmonitored by TLC. After completion of the reaction, the reaction wasquenched with saturated ammonium chloride solution. The mixture wasdiluted with ethyl acetate, washed with saturated ammonium chloridesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=500:1) to give WYC-301 (155 mg,79%). ¹H NMR (500 MHz, CDCl₃) δ 10.75 (s, 1H), 7.76 (d, J=8.2 Hz, 1H),7.43 (dd, J=7.7, 7.1 Hz, 7H), 7.37 (dd, J=9.3, 3.7 Hz, 4H), 7.21 (d,J=1.3 Hz, 1H), 7.09 (d, J=1.2 Hz, 1H), 6.97 (dd, J=8.2, 1.2 Hz, 1H),6.02 (t, J=4.6 Hz, 1H), 3.94 (s, 3H), 2.37 (d, J=4.7 Hz, 2H), 1.36 (s,6H). ¹³C NMR (126 MHz, CDCl₃) δ 170.27, 161.31, 146.42, 140.63, 138.99,134.24, 131.17, 130.83, 129.82, 129.20, 128.80, 128.54, 127.41, 127.38,124.18, 122.47, 120.36, 120.07, 111.98, 92.99, 87.93, 52.47, 38.85,33.94, 28.19. ESI(+)-MS: 409.3 [M+1]+.

Embodiment 40: ethyl4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate

WYC-301 (250 mg, 0.613 mmol) was added to a flask, followed by additionof sodium ethoxide (125 mg, 1.83 mmol) and 5 mL ethanol. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=100:1) to give WYC-302 (230 mg,92%). ¹H NMR (500 MHz, CDCl₃) δ 10.82 (s, 1H), 7.77 (d, J=8.2 Hz, 1H),7.45-7.39 (m, 3H), 7.38-7.34 (m, 4H), 7.19 (d, J=1.5 Hz, 1H), 7.07 (d,J=1.4 Hz, 1H), 6.95 (dd, J=8.2, 1.5 Hz, 1H), 6.01 (t, J=4.7 Hz, 1H),4.40 (q, J=7.1 Hz, 2H), 2.37 (d, J=4.7 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H),1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 169.92, 161.39, 146.40, 140.65,139.01, 134.25, 131.18, 130.70, 129.83, 129.20, 128.82, 128.55, 127.42,127.39, 124.19, 122.39, 120.37, 120.11, 112.25, 92.89, 87.99, 61.68,38.86, 33.96, 28.21, 14.32. ESI(+)-MS: 423.4 [M+1]+.

Embodiment 41: ethyl 2-fluoro-4-iodobenzoate

2-Fluoro-4-iodobenzoic acid (1.0 g, 3.76 mmol) was added to a flask,followed by addition of 10 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.5 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 4 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=15:1) to giveethyl 2-fluoro-4-iodobenzoate (990 mg, 90%). ¹H NMR (500 MHz, CDCl₃) δ7.62-7.57 (m, 1H), 7.52 (dd, J=8.3, 1.6 Hz, 1H), 7.49 (dd, J=9.9, 1.5Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). ¹³C NMR (126MHz, CDCl₃) δ 163.87, 163.84, 162.18, 160.06, 133.48, 133.45, 133.05,133.04, 126.54, 126.34, 118.76, 118.68, 99.59, 99.52, 61.59, 14.29.ESI(+)-MS: 294.1 [M+1]+.

Embodiment 42: ethyl2-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

6-Ethynyl-4,4-dimethylthiochroman (275 mg, 1.36 mmol) and ethyl2-fluoro-4-iodobenzoate (200 mg, 0.68 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (28.6 mg, 0.0408 mmol) and CuI(15.5 mg, 0.0816 mmol). After the flask was purged with argon for 3times to remove oxygen, 3 mL dry DMF and 0.3 mL dry Et₃N were added viasyringe. The reaction was continued at 80° C. for 6 h and monitored byTLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EA=200:1) to give WYC-303 (215 mg, 86%). ¹H NMR (500MHz, CDCl₃) δ 7.90 (t, J=7.8 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.32 (dd,J=8.1, 1.4 Hz, 1H), 7.28 (d, J=1.4 Hz, 1H), 7.25 (d, J=1.4 Hz, 1H), 7.19(dd, J=8.2, 1.7 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H),3.07-3.03 (m, 2H), 1.98-1.94 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.35 (s,6H). ¹³C NMR (126 MHz, CDCl₃) δ 164.12, 164.09, 162.75, 160.68, 142.32,134.45, 132.15, 132.14, 129.98, 129.20, 127.08, 127.05, 126.78, 119.79,119.60, 117.57, 93.98, 87.00, 86.98, 61.55, 37.25, 33.12, 30.09, 23.37,14.40. ESI(+)-MS: 369.4 [M+1]⁺.

Embodiment 43: 2-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoicacid

WYC-303 (15 mg, 0.04 mmol) was added to a flask, followed by addition ofsodium ethoxide (8.3 mg, 0.12 mmol) and 1 mL tetrahydrofuran. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=1:1) to give WYC-304 (11 mg,80%). ¹H NMR (500 MHz, CDCl₃) δ 7.99 (t, J=7.9 Hz, 1H), 7.53 (d, J=1.7Hz, 1H), 7.35 (dd, J=8.1, 1.5 Hz, 1H), 7.30 (dd, J=11.3, 1.4 Hz, 1H),7.19 (dd, J=8.1, 1.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.07-3.04 (m, 3H),1.98-1.95 (m, 2H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 167.53,163.34, 161.26, 142.36, 134.65, 132.80, 131.19, 131.11, 130.04, 129.25,127.25, 127.22, 126.81, 119.89, 119.70, 117.45, 116.98, 94.69, 86.92,37.24, 33.14, 30.09, 23.39. ESI(+)-MS: 339.3 [M+1]⁺.

Embodiment 44: ethyl4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-fluorobenzoate

6-Ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (180 mg, 0.7mmol) and ethyl 2-fluoro-4-iodo-benzoate (410 mg, 1.4 mmol) were addedto a flask, followed by addition of Pd(PPh₃)₂Cl₂ (30 mg, 0.042 mmol) andCuI (16.0 mg, 0.084 mmol). After the flask was purged with argon for 3times to remove oxygen, 5 mL dry DMF and 0.5 mL dry Et₃N were added viasyringe. The reaction was continued at 70° C. for 8 h and monitored byTLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EA=200:1) to give WYC-305 (215 mg, 72%). ¹H NMR (500MHz, CDCl₃) δ 7.87 (t, J=7.8 Hz, 1H), 7.44-7.39 (m, 7H), 7.37 (ddd,J=6.3, 3.4, 1.5 Hz, 4H), 7.29-7.26 (m, 1H), 7.24-7.18 (m, 2H), 6.02 (t,J=4.7 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 2.37 (d, J=4.7 Hz, 2H), 1.39 (t,J=7.1 Hz, 3H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 164.12, 164.09,162.70, 160.63, 146.67, 140.62, 138.95, 134.33, 132.08, 132.07, 131.17,129.92, 129.84, 129.20, 128.82, 128.57, 127.53, 127.41, 127.17, 127.14,124.25, 119.91, 119.77, 119.72, 118.51, 118.43, 93.66, 86.96, 86.94,61.55, 38.84, 33.98, 28.20, 14.39. ESI(+)-MS: 425.5 [M+1]⁺.

Embodiment 45:4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-fluorobenzicacid

WYC-305 (70 mg, 0.19 mmol) was added to a flask, followed by addition ofsodium ethoxide (26 mg, 0.3 8 mmol) and 2 mL tetrahydrofuran. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=2:1) to give WYC-306 (53 mg,75%). ¹H NMR (500 MHz, CDCl₃) δ 7.95 (t, J=7.9 Hz, 1H), 7.44-7.39 (m,7H), 7.39-7.35 (m, 4H), 7.30 (dd, J=8.2, 1.4 Hz, 1H), 7.24 (d, J=1.3 Hz,1H), 7.19 (d, J=1.5 Hz, 1H), 6.02 (t, J=4.7 Hz, 1H), 2.37 (d, J=4.7 Hz,2H), 1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 167.97, 163.32, 161.23,146.83, 140.60, 138.92, 134.36, 132.74, 131.22, 129.24, 128.83, 128.58,127.57, 127.43, 127.36, 127.33, 124.29, 120.02, 119.83, 119.64, 116.90,94.43, 86.86, 38.84, 34.00, 28.20. ESI(+)-MS: 395.4 [M+1]⁺.

Embodiment 46: ethyl 3-fluoro-4-iodobenzoate

3-Fluoro-4-iodobenzoic acid (0.95 g, 3.57 mmol) was added to a flask,followed by addition of 5 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.3 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 4 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=15:1) to giveethyl 3-fluoro-4-iodobenzoate (920 mg, 88%). ¹H NMR (500 MHz, CDCl₃) δ7.80 (dd, J=8.2, 6.2 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.53 (dd,J=8.2, 1.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 164.99, 164.97, 162.64, 160.67, 139.61, 139.59,132.94, 132.89, 126.51, 126.48, 116.46, 116.26, 87.88, 87.67, 61.65,14.33. ESI(+)-MS: 295.1 [M+1]+.

Embodiment 47: ethyl 4-iodo-3-nitrobenzoate

4-Iodo-3-nitrobenzoic acid (1.9 g, 6.48 mmol) was added to a flask,followed by addition of 10 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.6 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 6 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=10:1) to giveethyl 4-iodo-3-nitrobenzoate (1.88 g, 90.5%). ¹H NMR (500 MHz, CDCl₃) δ8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 2.0 Hz,1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz,CDCl₃) δ 164.03, 153.15, 142.33, 133.47, 131.96, 125.98, 92.02, 62.16,14.29. ESI(+)-MS: 322.1 [M+1]⁺.

Embodiment 48: ethyl3-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and ethyl3-fluoro-4-iodobenzoate (294 mg, 1.0 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (84 mg, 0.12 mmol) and CuI (46.0mg, 0.24 mmol). After the flask was purged with argon for 3 times toremove oxygen, 5 mL dry DMF and 0.5 mL dry Et₃N were added via syringe.The reaction was continued at 70° C. for 8 h and monitored by TLC. Aftercompletion of the reaction, the reaction was quenched with saturatedammonium chloride solution. The mixture was diluted with ethyl acetate,washed with saturated ammonium chloride solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EA=500:3) to give WYC-307 (250 mg, 68%). ¹H NMR (500MHz, CDCl₃) δ 7.81 (dd, J=8.0, 1.3 Hz, 1H), 7.76 (dd, J=9.8, 1.3 Hz,1H), 7.56 (dd, J=11.1, 4.2 Hz, 2H), 7.22 (dd, J=8.1, 1.6 Hz, 1H), 7.08(d, J=8.1 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 3.05 (dd, J=7.1, 5.1 Hz, 2H),1.98-1.94 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). ¹³C NMR (126MHz, CDCl₃) δ 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26,133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12, 117.73,117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29,33.13, 30.09, 23.38, 14.42. ESI(+)-MS: 369.3 [M+1]⁺.

Embodiment 49: ethyl3-nitro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and ethyl3-nitro-4-iodobenzoate (303 mg, 1.0 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (84 mg, 0.12 mmol) and CuI (46.0mg, 0.24 mmol). After the flask was purged with argon for 3 times toremove oxygen, 5 mL dry DMF and 0.5 mL dry Et₃N were added via syringe.The reaction was continued at 70° C. for 8 h and monitored by TLC. Aftercompletion of the reaction, the reaction was quenched with saturatedammonium chloride solution. The mixture was diluted with ethyl acetate,washed with saturated ammonium chloride solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EA=50:1) to give WYC-308 (384 mg, 97%). ¹H NMR (400MHz, CDCl₃) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (dd, J=8.1, 1.6 Hz, 1H), 7.74(d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.23-7.25 (m, 1H), 7.08 (d, J=8.2 Hz,1H), 4.42 (q, J=7.1 Hz, 2H), 3.04 (dd, J=7.2, 4.9 Hz, 2H), 1.98-1.85 (m,2H), 1.41 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ164.34, 149.33, 142.43, 135.66, 134.63, 133.24, 130.35, 130.30, 129.65,126.86, 126.01, 123.20, 117.23, 101.65, 84.50, 62.11, 37.16, 33.12,30.04, 23.43, 14.43. ESI(+)-MS: 396.2 [M+1]⁺.

Embodiment 50: 3-nitro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoicacid

WYC-308 (100 mg, 0.25 mmol) was added to a flask, followed by additionof sodium ethoxide (35 mg, 0.5 mmol) and 2 mL ethanol. Then the reactionwas continued at room temperature overnight and monitored by TLC. Aftercompletion of the reaction, the reaction solution was neutralized toneutral with acid resin and filtered, the filtrate was diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (DCM:MeOH=20:1) to give WYC-309 (83 mg, 90.4%). ¹HNMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.78 (d,J=8.0 Hz, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 7.09 (d, J=8.1 Hz, 1H),3.10-3.04 (m, 2H), 2.00-1.93 (m, 2H), 1.36 (s, 6H). ¹³C NMR (101 MHz,CDCl₃) δ 168.58, 149.36, 142.46, 135.91, 134.83, 133.69, 130.42, 129.73,126.89, 126.73, 124.17, 117.12, 102.51, 84.56, 37.14, 33.13, 30.11,30.04, 23.45. ESI(+)-MS: 3 [M+1]⁺.

Embodiment 51: 3-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoicacid

WYC-307 (332 mg, 0.9 mmol) was added to a flask, followed by addition ofsodium ethoxide (83 mg, 1.2 mmol) and 7 mL ethanol. Then the reactionwas continued at room temperature overnight and monitored by TLC. Aftercompletion of the reaction, the reaction solution was neutralized toneutral with acid resin and filtered, the filtrate was diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EA=1:1) to give WYC-310 (303 mg, 99%). ¹H NMR(400 MHz, CDCl₃) δ 7.85 (dd, J=8.1, 1.2 Hz, 1H), 7.80 (dd, J=9.7, 1.1Hz, 1H), 7.61-7.56 (m, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.2 Hz,1H), 7.07 (d, J=8.2 Hz, 1H), 3.11-2.99 (m, 2H), 1.99-1.90 (m, 2H), 1.34(s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 169.23, 163.46, 160.95, 142.34,134.64, 133.45, 130.03, 129.32, 126.79, 125.79, 117.62, 117.27, 117.04,110.16, 98.73, 81.63, 37.28, 33.15, 30.10, 23.40. ESI(+)-MS: 341.2[M+1]+.

Embodiment 52: ethyl3-nitro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-308 (100 mg, 0.25 mmol) was added to a flask, followed by additionof 5 mL dry dichloromethane. After the mixture was cooled to 0° C. underan ice bath, mCPBA (60 mg, 0.25 mmol) was added. Then the reaction wascontinued for 1 h under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=3:1) to give WYC-311 (92 mg, 88%). ¹H NMR (500 MHz, CDCl₃) δ8.73 (d, J=1.6 Hz, 1H), 8.26 (dd, J=8.1, 1.7 Hz, 1H), 7.80 (dd, J=13.0,8.1 Hz, 2H), 7.66 (d, J=1.5 Hz, 1H), 7.57 (dd, J=8.0, 1.6 Hz, 1H), 4.44(q, J=7.1 Hz, 2H), 3.23 (ddd, J=12.8, 10.3, 2.3 Hz, 1H), 3.12 (ddd,J=13.1, 9.1, 2.3 Hz, 1H), 2.44 (ddd, J=15.1, 10.3, 2.3 Hz, 1H), 1.91(ddd, J=15.1, 9.0, 2.3 Hz, 1H), 1.48 (s, 3H), 1.43 (t, J=7.1 Hz, 3H),1.35 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 164.10, 149.65, 145.16, 139.98,134.95, 133.42, 131.67, 131.30, 130.53, 130.26, 126.01, 125.35, 122.13,98.90, 86.27, 62.24, 43.39, 34.67, 31.36, 31.24, 29.89, 14.40.ESI(+)-MS: 412.2 [M+1]⁺.

Embodiment 53: ethyl3-fluoro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

1-Oxo-6-ethynyl-4,4-dimethylthiochroman (223 mg, 1.2 mmol) and ethyl3-fluoro-4-iodobenzoate (200 mg, 0.8 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (32 mg, 0.0459 mmol) and CuI (17.5mg, 0.0918 mmol). After the flask was purged with argon for 3 times toremove oxygen, 3 mL dry DMF and 0.3 mL dry Et₃N were added via syringe.Then the reaction was continued at 75° C. for 8 h and monitored by TLC.After completion of the reaction, the reaction solution was cooled toroom temperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=3:2) to give WYC-312 (254 mg, 82.5%). ¹H NMR (500 MHz, CDCl₃)δ 7.84 (dd, J=8.0, 1.5 Hz, 1H), 7.81-7.75 (m, 2H), 7.63-7.58 (m, 2H),7.54 (dd, J=8.0, 1.6 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.22 (ddd, J=12.9,10.4, 2.3 Hz, 1H), 3.11 (ddd, J=13.1, 8.9, 2.4 Hz, 1H), 2.46 (ddd,J=15.1, 10.4, 2.3 Hz, 1H), 1.91 (ddd, J=15.1, 8.9, 2.3 Hz, 1H), 1.49 (s,3H), 1.41 (t, J=7.1 Hz, 4H), 1.35 (s, 4H). ¹³C NMR (126 MHz, CDC133) δ165.04, 163.42, 161.41, 145.01, 139.21, 133.49, 132.58, 132.52, 132.26,132.18, 131.33, 130.29, 130.27, 128.67, 128.57, 125.87, 125.22, 125.19,116.78, 116.60, 116.06, 115.93, 96.03, 96.00, 84.16, 61.73, 43.34,34.62, 31.36, 31.22, 29.81, 14.40. ESI(+)-MS: 385.2 [M+1]+.

Embodiment 54: ethyl 2,3-difluoro-4-iodobenzoate

2,3-Difluoro-4-iodobenzoic acid (0.5 g, 1.76 mmol) was added to a flask,followed by addition of 4 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.3 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 6 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=10:1) to giveethyl 2,3-difluoro-4-iodobenzoate (0.48 g, 87%). ¹H NMR (500 MHz, CDCl₃)δ 7.55 (ddd, J=8.4, 5.2, 1.8 Hz, 1H), 7.44 (ddd, J=8.4, 6.3, 1.8 Hz,1H), 4.38 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz,CDCl₃) δ 163.13, 163.10, 163.08, 152.43, 152.31, 150.69, 150.56, 150.46,150.35, 148.56, 148.44, 133.21, 133.17, 127.48, 127.44, 121.24, 121.18,88.19, 88.01, 61.98, 14.27. ESI(+)-MS: 313.1 [M+1]+.

Embodiment 55: ethyl2,3-difluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

Ethyl 2,3-difluoro-4-iodobenzoate (200 mg, 0.64 mmol) and6-ethynyl-4,4-dimethylthiochroman (195 mg, 0.96 mmol) were added to aflask, followed by addition of Pd(PPh₃)₂Cl₂ (20 mg, 0.0288 mmol) and CuI(11 mg, 0.0576 mmol). After the flask was purged with argon for 3 timesto remove oxygen, 2 mL dry DMF and 0.2 mL dry Et₃N were added viasyringe. Then the reaction was continued at 75° C. for 8 h and monitoredby TLC. After completion of the reaction, the reaction solution wascooled to room temperature and the reaction was quenched with saturatedammonium chloride solution. The mixture was diluted with ethyl acetate,washed with saturated ammonium chloride solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=100:1) to give WYC-313 (215 mg, 82%). ¹H NMR(500 MHz, CDCl₃) δ 7.65 (ddd, J=8.3, 6.5, 1.8 Hz, 1H), 7.54 (d, J=1.7Hz, 1H), 7.28 (ddd, J=8.0, 4.9, 1.9 Hz, 1H), 7.21 (dd, J=8.2, 1.8 Hz,1H), 7.08 (d, J=8.2 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.07-3.03 (m, 2H),1.97-1.93 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). ¹³C NMR (126MHz, CDCl₃) δ 163.34, 152.40, 152.29, 151.69, 151.58, 150.38, 150.27,149.60, 149.49, 142.32, 134.92, 129.98, 129.27, 127.01, 126.98, 126.76,126.01, 125.97, 120.13, 120.07, 118.59, 118.51, 117.25, 99.26, 99.23,80.63, 80.60, 61.87, 37.18, 33.09, 30.02, 23.35, 14.33. ESI(+)-MS: 387.2[M+1]⁺.

Embodiment 56:2,3-difluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic acid

WYC-313 (84 mg, 0.218 mmol) was added to a flask, followed by additionof sodium ethoxide (44.4 mg, 0.653 mmol) and 2 mL ethanol. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=1:1) to give WYC-314 (68 mg,87.5%). ¹H NMR (500 MHz, pyridine) δ 8.01 (t, J=7.4 Hz, 1H), 7.82 (s,1H), 7.45 (t, J=7.2 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.1 Hz,1H), 2.95-2.89 (m, 2H), 1.78-1.71 (m, 2H), 1.19 (s, 6H). ESI(−)-MS:357.2 [M−1]⁻.

Embodiment 57: ethyl2,3-difluoro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-313 (90 mg, 0.233 mmol) was added to a flask, followed by additionof 5 mL dry dichloromethane. After the mixture was cooled to 0° C. underan ice bath, mCPBA (58 mg, 0.233 mmol) was added. Then the reaction wascontinued for 1 h under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=3:1) to give WYC-315 (76 mg, 78%). ¹H NMR (500 MHz, CDCl₃) δ7.76 (d, J=8.0 Hz, 1H), 7.71-7.65 (m, 1H), 7.62 (s, 1H), 7.53 (dd,J=8.0, 0.8 Hz, 1H), 7.32 (dd, J=10.4, 3.9 Hz, 1H), 4.41 (q, J=7.1 Hz,2H), 3.26-3.18 (m, 1H), 3.15-3.07 (m, 1H), 2.44 (ddd, J=14.8, 10.3, 2.0Hz, 1H), 1.90 (ddd, J=15.1, 8.9, 2.0 Hz, 1H), 1.47 (s, 3H), 1.40 (t,J=7.1 Hz, 3H), 1.34 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 163.22, 163.20,163.17, 152.69, 152.58, 151.65, 151.54, 150.66, 150.55, 149.55, 145.10,139.57, 131.40, 130.30, 130.27, 127.25, 127.22, 126.15, 126.12, 125.41,121.05, 120.99, 117.60, 117.59, 117.50, 117.48, 97.09, 97.05, 82.93,82.90, 62.02, 43.34, 34.63, 31.34, 31.21, 29.82, 14.32. ESI(+)-MS: 403.1[M+1]⁺.

Embodiment 58: methyl 3-acetamido-4-iodobenzoate

Methyl 3-amino-4-iodobenzoate (1.5 g, 5.43 mmol) was added to a flask,followed by addition of 20 mL dry dichloromethane and 4.5 mL drytriethylamine, then 0.77 mL acetyl chloride was added dropwise under anice bath. The reaction was continued at room temperature overnight andmonitored by TLC. After completion of the reaction, the reaction wasquenched with methanol. The mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=10:1) to give methyl 3-acetamido-4-iodobenzoate(1.34 g, 77.5%). ¹H NMR (500 MHz, CDCl₃) δ 8.75 (s, 1H), 7.86 (d, J=8.3Hz, 1H), 7.54-7.39 (m, 2H), 3.90 (s, 3H), 2.25 (s, 3H). ¹³C NMR (126MHz, CDCl₃) δ 168.29, 166.28, 138.97, 138.54, 131.46, 126.74, 122.89,96.10, 52.44, 24.78. ESI(+)-MS: 320.1 [M+1]⁺.

Embodiment 59: methyl3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

Methyl 3-acetamido-4-iodobenzoate (319 mg, 1 mmol) and6-ethynyl-4,4-dimethylthiochroman (304 mg, 1.5 mmol) were added to aflask, followed by addition of Pd(PPh₃)₂Cl₂ (47 mg, 0.0675 mmol) and CuI(26 mg, 0.135 mmol). After the flask was purged with argon for 3 timesto remove oxygen, 5 mL dry DMF and 0.3 mL dry Et₃N were added viasyringe. Then the reaction was continued at 70° C. for 8 h and monitoredby TLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=10:1) to give WYC-316 (298 mg, 76%). ¹H NMR(500 MHz, CDCl₃) δ 9.00 (s, 1H), 7.97 (s, 1H), 7.74 (dd, J=8.1, 1.2 Hz,1H), 7.57-7.50 (m, 2H), 7.18 (dd, J=8.1, 1.7 Hz, 1H), 7.10 (d, J=8.1 Hz,1H), 3.91 (s, 3H), 3.10-3.02 (m, 2H), 2.26 (s, 3H), 1.98-1.93 (m, 2H),1.35 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 168.23, 166.55, 142.53, 138.77,135.02, 131.51, 130.80, 129.71, 128.90, 126.92, 124.65, 120.35, 117.03,110.11, 99.62, 83.25, 52.42, 37.09, 33.11, 30.02, 25.03, 23.36.ESI(+)-MS: 394.2 [M+1]⁺.

Embodiment 60: ethyl3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

WYC-316 (56 mg, 0.142 mmol) was added to a flask, followed by additionof sodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=20:1) to give WYC-317 (48 mg,83%). ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 7.97 (s, 1H), 7.75 (d,J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.18 (dd, J=8.1, 1.3 Hz, 1H),7.10 (d, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.09-3.02 (m, 2H), 2.26(s, 3H), 1.98-1.94 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). ¹³CNMR (126 MHz, CDCl₃) δ 168.22, 166.08, 142.53, 138.76, 135.00, 131.47,131.21, 129.72, 128.91, 126.93, 124.64, 120.38, 117.07, 110.12, 99.54,83.31, 61.39, 37.11, 33.12, 30.04, 25.03, 23.36, 14.44. ESI(+)-MS: 408.2[M+1]⁺.

Embodiment 61: ethyl3-acetamido-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-317 (86 mg, 0.211 mmol) was added to a flask, followed by additionof 2 mL dry dichloromethane. After the mixture was cooled to 0° C. underan ice bath, mCPBA (37 mg, 0.211 mmol) was added. Then the reaction wascontinued for 1 h under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:1) to give WYC-318 (80 mg, 98.6%). ¹H NMR (500 MHz, CDCl₃₃)δ 8.98 (s, 1H), 7.93 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.61 (d, J=1.3 Hz,1H), 7.57 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.0, 1.3 Hz, 1H), 4.38 (q,J=7.1 Hz, 2H), 3.24 (dd, J=17.2, 6.3 Hz, 1H), 3.17-3.09 (m, 1H), 2.45(ddd, J=14.8, 10.3, 1.9 Hz, 1H), 2.27 (s, 3H), 1.91 (ddd, J=15.1, 8.9,2.0 Hz, 1H), 1.48 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 3H). ¹³C NMR(126 MHz, CDCl₃) δ 168.29, 165.92, 145.31, 139.07, 131.97, 131.91,131.19, 130.44, 129.98, 125.33, 124.80, 124.76, 120.86, 115.83, 97.48,85.94, 61.51, 43.40, 34.66, 31.36, 31.27, 29.79, 14.43. ESI(+)-MS: 424.1[M+1]+.

Embodiment 62:3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic acid

WYC-316 (63 mg, 0.16 mmol) was added to a flask, followed by addition ofsodium ethoxide (14 mg, 0.2 mmol), 2 mL tetrahydrofuran and 0.2 mLwater. Then the reaction was continued at room temperature overnight andmonitored by TLC. After completion of the reaction, the reactionsolution was neutralized to neutral with acid resin and filtered, thefiltrate was diluted with ethyl acetate, washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=1:4) to giveWYC-319 (34 mg, 56%). ESI(+)-MS: 380.2 [M+1]⁺.

Embodiment 63: ethyl 5-bromopyrazin-2-carboxylate

5-Bromopyrazin-2-carboxylic acid (1.0 g, 5 mmol) was added to a flask,followed by addition of 5 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.3 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 6 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=50:1) to giveethyl 5-bromopyrazin-2-carboxylate (0.42 g, 37%). ¹H NMR (500 MHz,CDCl₃) δ 9.01 (d, J=1.3 Hz, 1H), 8.76 (d, J=1.3 Hz, 1H), 4.47 (q, J=7.1Hz, 2H), 1.41 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 163.39,147.30, 146.31, 144.65, 141.89, 62.67, 14.30. ESI(+)-MS: 231.2 [M+1]⁺.

Embodiment 64: ethyl2-((4,4-dimethyl-1,1-dioxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate

WYC-209 (1.1 g, 3 mmol) was added to a flask, followed by addition of 20mL dry dichloromethane. After the mixture was cooled to 0° C. under anice bath, mCPBA (0.663 g, 3.6 mmol) was added. Then the reaction wascontinued for 10 min under the ice bath and another 3 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:5) to give WYC-320 (0.99 g, 89%). ¹H NMR (500 MHz, CDCl₃) δ9.29 (s, 2H), 7.94 (d, J=8.2 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.68 (dd,J=8.2, 1.5 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.46-3.37 (m, 2H), 2.45-2.39(m, 2H), 1.44 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 163.22, 158.51,155.10, 145.17, 138.59, 132.27, 131.31, 125.41, 124.24, 122.74, 89.85,88.71, 62.32, 47.06, 35.49, 34.47, 30.71, 14.35. ESI(+)-MS: 385.4[M+1]⁺.

Embodiment 65: methyl3-acetamido-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-316 (107 mg, 0.272 mmol) was added to a flask, followed by additionof 3.5 mL dry dichloromethane. After the mixture was cooled to 0° C.under an ice bath, mCPBA (67.3 mg, 0.272 mmol) was added. Then thereaction was continued for 1 h under the ice bath and another 2 h atroom temperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:1) to give WYC-321 (84 mg, 78%). ¹H NMR (500 MHz, CDCl₃) δ8.97 (s, 1H), 7.96 (s, 1H), 7.80-7.72 (m, 2H), 7.60 (d, J=1.4 Hz, 1H),7.56 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.0, 1.3 Hz, 1H), 3.90 (s, 3H), 3.14(ddt, J=12.9, 8.9, 6.4 Hz, 2H), 2.45 (ddd, J=14.8, 10.3, 1.7 Hz, 1H),2.26 (s, 3H), 1.90 (ddd, J=15.0, 8.9, 1.9 Hz, 1H), 1.47 (s, 3H), 1.34(s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 168.28, 166.37, 145.28, 139.65,139.09, 131.94, 131.52, 131.18, 130.41, 129.95, 125.29, 124.74, 120.91,115.97, 97.52, 85.89, 52.49, 43.37, 34.63, 31.32, 31.25, 29.76, 24.99.ESI(+)-MS: 410.3 [M+1]+.

Embodiment 66: ethyl5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-carboxylate

Ethyl 5-bromopyrazin-2-carboxylate (600 mg, 2.61 mmol) and6-ethynyl-4,4-dimethylthiochroman (635 mg, 3.13 mmol) were added to aflask, followed by addition of Pd(PPh₃)₂Cl₂ (66 mg, 0.094 mmol) and CuI(36 mg, 0.188 mmol). After the flask was purged with argon for 3 timesto remove oxygen, 6 mL dry DMF and 0.4 mL dry Et₃N were added viasyringe. Then the reaction was continued at 80° C. for 8 h and monitoredby TLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=50:1) to give WYC-322 (656 mg, 71.5%). ¹H NMR(500 MHz, CDCl₃) δ 9.20 (d, J=1.4 Hz, 1H), 8.76 (d, J=1.4 Hz, 1H), 7.58(d, J=1.7 Hz, 1H), 7.23 (dd, J=8.2, 1.8 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H),4.46 (q, J=7.1 Hz, 2H), 3.02-2.97 (m, 2H), 1.92-1.87 (m, 2H), 1.41 (t,J=7.1 Hz, 3H), 1.29 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 163.65, 146.68,145.70, 143.08, 142.31, 140.30, 136.14, 130.54, 129.51, 126.74, 116.00,97.55, 85.68, 62.37, 36.91, 32.99, 29.89, 23.27, 14.31. ESI(+)-MS: 353.5[M+1]+.

Embodiment 67:5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-carboxylic acid

WYC-322 (50 mg, 0.14 mmol) was added to a flask, followed by addition ofsodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then the reactionwas continued at room temperature overnight and monitored by TLC. Aftercompletion of the reaction, the reaction solution was neutralized toneutral with acid resin and filtered, the filtrate was diluted withethyl acetate, washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (DCM:MeOH=15:1) to give WYC-323 (43 mg, 95%). ¹HNMR (500 MHz, pyridine) δ 9.65 (s, 1H), 9.05 (s, 1H), 7.84 (d, J=1.4 Hz,1H), 7.41 (dd, J=8.1, 1.4 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 2.98-2.88 (m,2H), 1.81-1.72 (m, 2H), 1.19 (s, 6H). ¹³C NMR (126 MHz, pyridine) δ166.73, 147.26, 146.43, 143.36, 142.96, 142.56, 136.52, 130.88, 129.89,127.24, 116.79, 96.42, 86.89, 36.94, 33.05, 29.59, 23.30. ESI(+)-MS:325.2 [M+1]⁺.

Embodiment 68: ethyl5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrazin-2-carboxylate

WYC-322 (100 mg, 0.284 mmol) was added to a flask, followed by additionof 3.5 mL dry dichloromethane. After the mixture was cooled to 0° C.under an ice bath, mCPBA (49 mg, 0.284 mmol) was added. Then thereaction was continued for 1 h under the ice bath and another 2 h atroom temperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:2) to give WYC-324 (78 mg, 75%). ¹H NMR (500 MHz, CDCl₃₃) δ9.29 (d, J=1.4 Hz, 1H), 8.87 (d, J=1.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H),7.71 (d, J=1.5 Hz, 1H), 7.61 (dd, J=8.1, 1.6 Hz, 1H), 4.52 (q, J=7.1 Hz,2H), 3.29-3.06 (m, 2H), 2.43 (ddd, J=15.1, 10.2, 2.3 Hz, 1H), 1.91 (ddd,J=15.1, 9.2, 2.3 Hz, 1H), 1.47 (dd, J=8.8, 5.5 Hz, 6H), 1.34 (s, 3H).¹³C NMR (126 MHz, CDCl₃) δ 163.62, 147.07, 145.93, 145.25, 142.41,141.29, 140.60, 132.05, 130.63, 130.25, 124.32, 94.92, 87.36, 62.70,43.44, 34.73, 31.35, 31.25, 29.91, 14.41. ESI(+)-MS: 396.2 [M+1]⁺.

Embodiment 69: ethyl 2-chloro-4-iodobenzoate

2-Chloro-4-iodobenzoic acid (1.0 g, 3.55 mmol) was added to a flask,followed by addition of 7 mL anhydrous ethanol under argon atmosphere.The mixture was cooled to 0° C. under an ice bath, then 0.4 mLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 5 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=7:1) to give ethyl2-chloro-4-iodobenzoate (0.98 g, 89%). ¹H NMR (500 MHz, CDCl₃) δ 7.82(d, J=1.6 Hz, 1H), 7.65 (dd, J=8.2, 1.6 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H),4.38 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃)δ 165.22, 139.57, 135.95, 134.63, 132.47, 129.91, 98.35, 61.87, 14.32.ESI(+)-MS: 311.3 [M+1]⁺.

Embodiment 70: ethyl2-chloro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate

Ethyl 2-chloro-4-iodobenzoate (310 mg, 1 mmol) and6-ethynyl-4,4-dimethylthiochroman (244 mg, 1.2 mmol) were added to aflask, followed by addition of Pd(PPh₃)₂Cl₂ (28 mg, 0.04 mmol) and CuI(11.4 mg, 0.06 mmol). After the flask was purged with argon for 3 timesto remove oxygen, 3 mL dry DMF and 0.3 mL dry Et₃N were added viasyringe. Then the reaction was continued at 80° C. for 8 h and monitoredby TLC. After completion of the reaction, the reaction was quenched withsaturated ammonium chloride solution. The mixture was diluted with ethylacetate, washed with saturated ammonium chloride solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=50:1) to give WYC-325 (365 mg, 95%). ¹H NMR(500 MHz, CDCl₃) δ 7.81 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.52(d, J=1.7 Hz, 1H), 7.42 (dd, J=8.1, 1.5 Hz, 1H), 7.18 (dd, J=8.2, 1.8Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.06-3.02 (m,2H), 1.97-1.93 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). ¹³C NMR(126 MHz, CDCl₃) δ 165.27, 142.26, 134.37, 133.89, 133.65, 131.41,129.92, 129.38, 129.30, 129.14, 128.27, 126.72, 117.56, 93.73, 86.76,61.71, 37.21, 33.06, 30.04, 23.32, 14.33. ESI(+)-MS: 385.2 [M+1]⁺.

Embodiment 71: ethyl2-chloro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate

WYC-325 (100 mg, 0.26 mmol) was added to a flask, followed by additionof 3 mL dry dichloromethane. After the mixture was cooled to 0° C. underan ice bath, mCPBA (60 mg, 0.26 mmol) was added. Then the reaction wascontinued for 1 h under the ice bath and another 2 h at roomtemperature, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction was quenched with sodiumthiosulfate solution, the mixture was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography(PE:EtOAc=1:3) to give WYC-326 (86 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ7.79 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H),7.57 (d, J=1.5 Hz, 1H), 7.46 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (dd, J=8.1,1.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.17 (ddd, J=12.7, 10.5, 2.1 Hz,1H), 3.06 (ddd, J=13.1, 8.8, 2.2 Hz, 1H), 2.41 (ddd, J=14.9, 10.4, 2.1Hz, 1H), 1.85 (ddd, J=15.1, 8.8, 2.2 Hz, 1H), 1.43 (s, 3H), 1.36 (t,J=7.1 Hz, 3H), 1.30 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.05, 144.93,138.96, 133.81, 133.81, 131.36, 131.23, 130.19, 130.08, 130.05, 129.58,127.12, 125.66, 91.67, 89.03, 61.74, 43.16, 34.45, 31.20, 31.06, 29.59,14.22. ESI(+)-MS: 401.2 [M+1]⁺.

Embodiment 72: 2-chloro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoicacid

WYC-325 (100 mg, 0.26 mmol) was added to a flask, followed by additionof sodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then thereaction was continued at room temperature overnight and monitored byTLC. After completion of the reaction, the reaction solution wasneutralized to neutral with acid resin and filtered, the filtrate wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=1:2) to give WYC-327 (89 mg, 94%).¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.52 (d,J=1.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H),7.07 (d, J=8.1 Hz, 1H), 3.07-3.04 (m, 2H), 1.98-1.94 (m, 2H), 1.35 (s,6H). ¹³C NMR (126 MHz, CDCl₃) δ 170.29, 142.32, 134.90, 134.53, 134.00,132.52, 130.02, 129.51, 129.36, 129.25, 127.76, 126.79, 117.54, 94.44,86.79, 37.25, 33.12, 30.09, 23.39. ESI(+)-MS: 355.2 [M+1]⁺.

Embodiment 73:2-cyano-5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidine

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg,0.235 mmol) and 2-cyano-5-bromopyrimidine (49.9 mg, 0.271 mmol) wereadded to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02mmol) and CuI (5.6 mg, 0.03 mmol). After the flask was purged with argonfor 3 times to remove oxygen, 2 mL dry DMF and 0.14 mL dry Et₃N wereadded via syringe. Then the reaction was continued at 70° C. for 8 h andmonitored by TLC. After completion of the reaction, the reactionsolution was cooled to room temperature and the reaction was quenchedwith saturated ammonium chloride solution. The mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=10:0 to 10:1) to give WYC-329 (75 mg,77%). ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 2H), 7.52 (d, J=1.4 Hz, 1H),7.38-7.29 (m, 2H), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ¹³CNMR (101MHz, CDCl₃) δ 159.24, 147.92, 145.68, 141.75, 130.54, 129.00, 127.11,122.82, 117.86, 115.58, 101.75, 80.64, 77.35, 77.04, 76.72, 34.78,34.73, 34.59, 34.31, 31.77, 31.64. ESI(+)-MS: 338.4 [M+1]+.

Embodiment 74:2-amino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoicacid

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (100 mg,0.47 mmol) and 2-amino-4-iodobenzoic acid (141.8 mg, 0.54 mmol) wereadded to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (28 mg, 0.04mmol) and CuI (11.2 mg, 0.059 mmol). After the flask was purged withargon for 3 times to remove oxygen, 2 mL dry DMF and 0.28 mL dry Et₃Nwere added via syringe. Then the reaction was continued at 50° C. for 8h and monitored by TLC. After completion of the reaction, the reactionsolution was cooled to room temperature and the reaction was quenchedwith saturated ammonium chloride solution. The mixture was diluted withethyl acetate, washed with saturated ammonium chloride solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EtOAc=50:1 to 10:1) to give WYC-330 (97 mg,60%). ¹H NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.46 (s, 1H), 7.33 (d,J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 1.72(s, 4H), 1.30 (s, 6H), 1.29 (s, 6H). ESI(+)-MS: 348.3 [M+1]+.

Embodiment 75: ethyl2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-5-carboxylate

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg,0.235 mmol) and ethyl 2-chloropyrimidin-4-carboxylate (50.3 mg, 0.27mmol) were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (14mg, 0.02 mmol) and CuI (5.6 mg, 0.03 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 1 mL dry DMF and 0.14 mL dryEt₃N were added via syringe. Then the reaction was continued at 70° C.for 8 h and monitored by TLC. After completion of the reaction, thereaction solution was cooled to room temperature and the reaction wasquenched with saturated ammonium chloride solution. The mixture wasdiluted with ethyl acetate, washed with saturated ammonium chloridesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-331(67.2 mg, 79%). ¹H NMR (500 MHz, CDCl₃) δ 9.26 (s, 2H), 7.67 (d, J=1.7Hz, 1H), 7.45 (dd, J=8.2, 1.8 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.46 (q,J=7.1 Hz, 2H), 1.69 (s, 4H), 1.44 (t, J=7.1 Hz, 3H), 1.29 (s, 6H), 1.28(s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 163.42, 158.33, 155.80, 148.01,145.46, 131.77, 129.86, 126.94, 121.83, 117.66, 92.54, 87.31, 62.02,34.81, 34.77, 34.58, 34.31, 31.72, 31.60. ESI(+)-MS: 363.3 [M+1]⁺.

Embodiment 76: methyl3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (120 mg,0.566 mmol) and methyl 3-hydroxy-4-iodobenzoate (180.7 mg, 0.65 mmol)were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (33.7 mg,0.048 mmol) and CuI (13.5 mg, 0.072 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 3 mL dry DMF and 0.338 mL dryEt₃N were added via syringe. Then the reaction was continued at 70° C.for 8 h and monitored by TLC. After completion of the reaction, thereaction was quenched with saturated ammonium chloride solution. Themixture was diluted with ethyl acetate, washed with saturated ammoniumchloride solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=50:1 to 10:1) togive WYC-332 (118 mg, 58%). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.95(dd, J=8.2, 1.4 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.63 (dd, J=8.3, 1.9Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.01 (d, J=0.8Hz, 1H), 3.96 (s, 3H), 1.74 (s, 4H), 1.38 (s, 6H), 1.33 (d, J=4.9 Hz,6H). ¹³C NMR (126 MHz, cdcl₃) δ 167.34, 159.55, 154.18, 146.62, 145.60,133.81, 127.20, 127.09, 125.67, 124.35, 123.49, 122.72, 120.13, 112.70,100.54, 77.25, 76.99, 76.74, 52.10, 35.01, 34.90, 34.43, 34.42, 31.84,31.72. ESI(+)-MS: 363.2 [M+1]+.

Embodiment 77:2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)-5-cyanopyridine

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg,0.283 mmol) and 2-chloro-5-cyanopyridine (59.5 mg, 0.325 mmol) wereadded to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (16.8 mg, 0.024mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purged withargon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dry Et₃Nwere added via syringe. Then the reaction was continued at 70° C. for 8h and monitored by TLC. After completion of the reaction, the reactionwas quenched with saturated ammonium chloride solution. The mixture wasdiluted with ethyl acetate, washed with saturated ammonium chloridesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EtOAc=100:1 to 20:1) to give WYC-333(59 mg, 67%). ¹H NMR (500 MHz, CDCl₃) δ 8.86 (dd, J=2.1, 0.8 Hz, 1H),7.93 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (dd, J=8.2, 0.8 Hz, 1H), 7.58 (d,J=1.7 Hz, 1H), 7.36 (dd, J=8.2, 1.7 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H),1.69 (s, 4H), 1.29 (s, 6H), 1.29 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ152.56, 147.56, 147.09, 145.45, 139.13, 130.99, 129.26, 126.92, 126.59,118.07, 116.52, 107.95, 95.22, 86.91, 77.25, 76.99, 76.74, 34.81, 34.76,34.52, 34.28, 31.73, 31.61. ESI(+)-MS: 315.6 [M+1]⁺.

Embodiment 78: ethyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-carboxylate

WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL ethanol, followed byaddition of sodium ethoxide (9.7 mg, 0.143 mmol). The reaction wascontinued at room temperature overnight. After completion of thereaction, the reaction solution was neutralized to weak acidic with 1mol/L HCl, diluted with ethyl acetate, washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EA=1000:1 to 20:1) togive WYC-334 (15 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 2H), 7.47(d, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.69 (s,4H), 1.45 (t, J=7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H). ¹³C NMR (101MHz, CDCl₃) δ 163.53, 161.19, 146.22, 145.28, 129.93, 128.61, 126.82,119.29, 113.07, 94.57, 81.42, 77.35, 77.04, 76.72, 63.94, 34.91, 34.85,34.41, 34.25, 31.77, 31.68, 14.42. ESI(+)-MS: 362.3 [M+1]⁺.

Embodiment 79: methyl2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg,0.205 mmol) and Compound c (75.3 mg, 0.271 mmol) were added to a flask,followed by addition of Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) and CuI (5.6 mg,0.03 mmol). After the flask was purged with argon for 3 times to removeoxygen, 2 mL dry DMF and 0.14 mL dry Et₃N were added via syringe. Thenthe reaction was continued at 70° C. for 8 h and monitored by TLC. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature and the reaction was quenched with saturated ammoniumchloride solution. The mixture was diluted with ethyl acetate, washedwith saturated ammonium chloride solution and saturated sodium chloridesolution. The organic phase was dried over anhydrous sodium sulfate,filtered, concentrated and purified by flash column chromatography (PE)to give the product (45.2 mg, 61%). ¹H NMR (400 MHz, CDCl₃) δ 10.76 (s,1H), 7.80 (d, J=8.2 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J=0.8 Hz, 2H), 7.13(d, J=1.4 Hz, 1H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 3.96 (s, 3H), 1.69 (s,4H), 1.30 (s, 6H), 1.28 (s, 6H). ESI(+)-MS: 363.3 [M+1]⁺.

Embodiment 80:2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoicacid

The product (30 mg, 0.082 mmol) obtained in the previous step was addedto a flask, followed by addition of 2 mL 2.0 mol/L NaOH and 2 mLmethanol. The reaction was continued at 55° C. overnight. Aftercompletion of the reaction, the reaction solution was neutralized to pH5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed withsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EA=100:0 to 10:1) to give WYC-335 (26.3 mg,93%). ¹H NMR (400 MHz, DMSO) δ 7.80 (d, J=8.1 Hz, 1H), 7.53 (d, J=1.6Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.2, 1.6 Hz, 1H), 7.12-7.04(m, 2H), 1.65 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H). ¹³C NMR (101 MHz,DMSO) δ 171.27, 160.85, 146.07, 145.05, 130.58, 129.74, 129.16, 128.67,126.98, 122.01, 119.29, 118.76, 92.56, 87.48, 40.12, 39.91, 39.70,39.49, 39.29, 39.08, 38.87, 34.36, 34.25, 34.08, 33.89, 31.39, 31.32.ESI(−)-MS: 347.3 [M−1].

Embodiment 81:2-acetylamino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoicacid

WYC-330 (52 mg, 0.15 mmol) was added to a flask, followed by addition of1 mg DMAP, then 3 mL dry pyridine was added under argon atmosphere.After the mixture was cooled to 0° C. under an ice bath, 7.8 L acetylchloride was added dropwise, and the reaction was continued for 5 minunder the ice bath and another 5 h at room temperature, meanwhile TLCwas used to monitor the reaction. After completion of the reaction, thereaction was quenched with methanol. The mixture was diluted with ethylacetate, washed with 1 mol/L hydrochloric acid to remove pyridine, thenwashed with saturated sodium bicarbonate solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and purified by flash columnchromatography (PE:EtOAc=20:1) to give WYC-336 (39.5 mg, 85%). ¹H NMR(400 MHz, CDCl₃) δ 8.13 (d, J=8.1 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.60(dd, J=8.1, 1.5 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=1.0 Hz, 2H), 2.47 (s,3H), 1.69 (d, J=5.7 Hz, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(−)-MS:388.4 [M−1]⁻.

Embodiment 82: methyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylate

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg,0.283 mmol) and methyl 5-bromo-pyridin-2-carboxylate (70 mg, 0.325 mmol)were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (16.8 mg,0.024 mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dryEt₃N were added via syringe. Then the reaction was continued at 70° C.for 8 h and monitored by TLC. After completion of the reaction, thereaction solution was cooled to room temperature and the reaction wasquenched with saturated ammonium chloride solution. The mixture wasdiluted with ethyl acetate, washed with saturated ammonium chloridesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=100:1 to 20:1) to give the product(68.7 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 8.85 (dd, J=2.0, 0.7 Hz, 1H),8.12 (dd, J=8.1, 0.7 Hz, 1H), 7.94 (dd, J=8.1, 2.1 Hz, 1H), 7.51 (s,1H), 7.32 (d, J=1.0 Hz, 2H), 4.02 (d, J=4.5 Hz, 3H), 1.69 (d, J=5.5 Hz,4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(+)-MS: 348.2 [M+1]⁺.

Embodiment 83:5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylicacid

The product (50 mg, 0.143 mmol) obtained in the previous step was addedto a flask, followed by addition of 2 mL 2.0 mol/L NaOH and 2 mLmethanol. The reaction was continued at 55° C. overnight. Aftercompletion of the reaction, the reaction solution was neutralized to pH5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed withsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EA=20:1 to 5:1) to give WYC-337 (42.2 mg,88%). ¹H NMR (400 MHz, MeOD) δ 8.67 (s, 1H), 8.00 (d, J=7.9 Hz, 1H),7.94 (dd, J=8.1, 2.0 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.36 (d, J=8.2 Hz,1H), 7.30 (dd, J=8.2, 1.7 Hz, 1H), 1.73 (s, 4H), 1.31 (s, 6H), 1.29 (s,6H). ESI(+)-MS: 334.4 [M+1]⁺.

Embodiment 84: methyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-carboxylate

WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL methanol, followed byaddition of sodium methoxide (7.7 mg, 0.143 mmol). The reaction solutionwas stirred at room temperature overnight. After completion of thereaction, the reaction solution was neutralized to weak acidic with 1mol/L HCl, diluted with ethyl acetate, washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicphase was dried over anhydrous sodium sulfate, filtered, concentratedand purified by flash column chromatography (PE:EtOAc=100:1 to 20:1) togive WYC-338 (14.9 mg, 90%). ¹H NMR (500 MHz, CDCl₃) δ 8.64 (s, 2H),7.47 (d, J=1.2 Hz, 1H), 7.34-7.27 (m, 2H), 4.05 (s, 3H), 1.69 (s, 4H),1.30 (s, 6H), 1.28 (s, 6H). ESI(+)-MS: 348.4 [M+1]⁺.

Embodiment 85: ethyl2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate

WYC-335 (15 mg, 0.043 mmol) was added to a flask, followed by additionof 0.8 mL anhydrous ethanol under argon atmosphere. The mixture wascooled to 0° C. under an ice bath, then 3 μL concentrated sulfuric acidwas added dropwise. After completion of the dropwise addition, thereaction solution was heated to reflux and stirred for 4 h, meanwhileTLC was used to monitor the reaction. After completion of the reaction,the reaction solution was cooled to room temperature, treated with 1mol/L sodium hydroxide to neutralize sulfuric acid to make a neutralsolution, then washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, dried, and purified by flash columnchromatography (PE:EtOAc=100:1 to 10:1) to give WYC-339 (14 mg, 87%).ESI(+)-MS: 377.3 [M+1]⁺.

Embodiment 86: ethyl3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate

WYC-332 (50 mg, 0.143 mmol) was added to a flask, followed by additionof 2 mL 2.0 mol/L NaOH and 2 mL methanol. The reaction was continued at55° C. overnight. After completion of the reaction, the reactionsolution was neutralized to pH 5-6 with 1 mol/L HCl, diluted with ethylacetate, extracted, washed with saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered,concentrated and purified by flash column chromatography (PE:EA=20:1 to5:1) to give the corresponding carboxylic acid (47 mg, 87%). Thecorresponding carboxylic acid (25 mg, 0.072 mmol) was added to a flask,followed by addition of 1.5 mL anhydrous ethanol under argon atmosphere.After the mixture was cooled to 0° C. under an ice bath, 5 μLconcentrated sulfuric acid was added dropwise. After completion of thedropwise addition, the reaction solution was heated to reflux andstirred for 4 h, meanwhile TLC was used to monitor the reaction. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, treated with 1 mol/L sodium hydroxide to neutralizesulfuric acid to make a neutral solution, then washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered, dried,and purified by flash column chromatography (PE:EtOAc=50:1 to 10:1) togive WYC-340 (24 mg, 90%). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.95(dd, J=8.2, 1.4 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.63 (dd, J=8.3, 1.9Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.01 (d, J=0.8Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.73 (s, 4H), 1.43 (t, J=7.1 Hz, 3H),1.37 (s, 6H), 1.32 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 166.91, 159.50,154.23, 146.62, 145.62, 133.74, 127.23, 127.15, 126.07, 124.37, 123.49,122.73, 120.12, 112.68, 100.57, 60.95, 35.03, 34.92, 34.44, 31.86,31.74; ESI(+)-MS: 377.4 [M+1]⁺.

Embodiment 87: ethyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylate

WYC-337 (25 mg, 0.075 mmol) was added to a flask, followed by additionof 1.5 mL anhydrous ethanol under argon atmosphere. After the mixturewas cooled to 0° C. under an ice bath, 5 μL concentrated sulfuric acidwas added dropwise. After completion of the dropwise addition, thereaction solution was heated to reflux and stirred for 4 h, meanwhileTLC was used to monitor the reaction. After completion of the reaction,the reaction solution was cooled to room temperature, treated with 1mol/L sodium hydroxide to neutralize sulfuric acid to make a neutralsolution, then washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, dried, and purified by flash columnchromatography (PE:EtOAc=50:1 to 10:1) to give WYC-341 (24 mg, 90%). ¹HNMR (400 MHz, CDCl₃) δ 8.85 (dd, J=2.0, 0.6 Hz, 1H), 8.11 (dd, J=8.1,0.7 Hz, 1H), 7.92 (dd, J=8.1, 2.1 Hz, 1H), 7.50 (t, J=1.2, 1H), 7.34 (d,J=2.5 Hz, 1H), 7.26 (dd, J=8.4, 2.1 Hz, 3H), 4.49 (q, J=7.2 Hz, 2H),1.69 (s, 4H), 1.45 (t, J=6.8 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H).ESI(+)-MS: 362.7 [M+1]⁺.

Embodiment 88: methyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-carboxylate

6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg,0.283 mmol) and methyl 2-chloropyrazin-4-carboxylate (56 mg, 0.325 mmol)were added to a flask, followed by addition of Pd(PPh₃)₂Cl₂ (16.8 mg,0.024 mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purgedwith argon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dryEt₃N were added via syringe. Then the reaction was continued at 70° C.for 8 h and monitored by TLC. After completion of the reaction, thereaction solution was cooled to room temperature and the reaction wasquenched with saturated ammonium chloride solution. The mixture wasdiluted with ethyl acetate, washed with saturated ammonium chloridesolution and saturated sodium chloride solution. The organic phase wasdried over anhydrous sodium sulfate, filtered, concentrated and purifiedby flash column chromatography (PE:EA=100:1 to 20:1) to give the product(55 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 9.28 (d, J=1.4 Hz, 1H), 8.83 (d,J=1.4 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.40 (dd, J=8.2, 1.7 Hz, 1H),7.34 (d, J=8.2 Hz, 1H), 4.06 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.29(s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 164.18, 147.91, 146.83, 145.74,145.57, 143.39, 140.07, 131.12, 129.38, 127.01, 117.83, 97.82, 85.11,77.34, 77.23, 77.02, 76.70, 53.19, 34.80, 34.76, 34.58, 34.31, 31.75,31.62. ESI(+)-MS: 349.2 [M+1]+.

Embodiment 89: ethyl5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-carboxylate

The product (35 mg, 0.1 mmol) obtained in the previous step was added toa flask, followed by addition of 1.5 mL 2.0 mol/L NaOH and 1.5 mLmethanol. The reaction was continued at 55° C. overnight. Aftercompletion of the reaction, the reaction solution was neutralized to pH5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed withsaturated sodium chloride solution. The organic phase was dried overanhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography (PE:EA=20:1 to 5:1) to give the correspondingcarboxylic acid (28.3 mg, 85%). The corresponding carboxylic acid (25mg, 0.075 mmol) was added to a flask, followed by addition of 1.5 mLanhydrous ethanol under argon atmosphere. After the mixture was cooledto 0° C. under an ice bath, 5 μL concentrated sulfuric acid was addeddropwise. After completion of the dropwise addition, the reactionsolution was heated to reflux and stirred for 4 h, meanwhile TLC wasused to monitor the reaction. After completion of the reaction, thereaction solution was cooled to room temperature, treated with 1 mol/Lsodium hydroxide to neutralize sulfuric acid to make a neutral solution,then washed with saturated sodium bicarbonate solution and saturatedsodium chloride solution. The organic phase was dried over anhydroussodium sulfate, filtered, dried, and purified by flash columnchromatography (PE:EtOAc=50:1 to 10:1) to give WYC-342 (20 mg, 75%). ¹HNMR (400 MHz, CDCl₃) δ 9.26 (d, J=1.4 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.2, 1.7 Hz, 1H), 7.32 (d, J=8.2 Hz,1H), 4.51 (q, J=7.1 Hz, 2H), 1.68 (s, 4H), 1.45 (t, J=7.1 Hz, 3H), 1.29(s, 6H), 1.27 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 163.72, 147.84,146.83, 145.72, 145.53, 143.21, 140.41, 131.09, 129.37, 127.00, 117.87,97.61, 85.15, 77.38, 77.07, 76.75, 62.42, 34.81, 34.76, 34.56, 34.30,31.75, 31.62. ESI(+)-MS: 363.6 [M+1]⁺.

Effect Embodiment 1: In Vitro Inhibitory Activity on the Proliferationof Tumor-Repopulating Cells (TRCs)

B16-F1 Melanoma cells were incubated with 3D fibrin gel medium (90-Pa)for 5 days, and the desired tumor-repopulating cells of melanoma werescreened (Nat. Mater. 2012, 11, 734). Subsequently, the culture mediumwas respectively treated with collagenase and neutral protease II, andthe tumor-repopulating cells of B16-F1 melanoma were released, then theobtained repopulating cells were transferred to a freshly preparedmedium to be resuspended and maintained at single-cell state. Thetumor-repopulating cells of B16-F1 melanoma were inoculated in 3D fibringel medium (90-Pa) for 5 days, with 0.1% DMSO as the negative controlgroup, Tazarotene and Bexarotene as the positive control drugsrespectively, the drug was added at a concentration of 1 μM and thecells were incubated for 5 days. The colony tumor size was measured andcalculated, and the inhibition rate of each drug on thetumor-repopulating cells of B16-F1 melanoma was calculated. The resultsof inhibitory activity of the compound of the present invention on theproliferation of tumor-repopulating cells of B16-F1 melanoma were shownin Table 2 below.

TABLE 2 Inhibitory activity on the proliferation of tumor- repopulatingcells (TRCs) of B16-F1 melanoma Inhibition rate on TRCs of B16-F1melanoma at a Compound number concentration of 10 μM (%) WYC-101 76.0WYC-102 59.1 WYC-103 86.8 WYC-105 64.1 WYC-106 72.4 WYC-107 75.0 WYC-20285.3 WYC-203 90.5 WYC-204 25.6 WYC-205 91.5 WYC-206 77.2 WYC-207 92.5WYC-208 27.7 WYC-209 98.8 WYC-209A 98.9 WYC-209B 98.7 WYC-210 18.1WYC-212 93.2 WYC-213 71.1 WYC-214 51.6 WYC-215 80.2 WYC-216 84.0 WYC-21790.3 WYC-218 90.4 WYC-219 64.8 WYC-220 65.5 WYC-301 34.4 WYC-302 21.9WYC-303 71.1 WYC-304 75.8 WYC-305 26.0 WYC-306 15.2 WYC-307 70.3 WYC-30871.9 WYC-309 56.8 WYC-310 76.8 WYC-311 80.2 WYC-312 71.0 WYC-313 62.2WYC-314 70.1 WYC-315 70.1 WYC-316 76.2 WYC-317 86.4 WYC-318 60.0 WYC-31965.8 WYC-320 92.6 WYC-321 78.2 WYC-322 78.8 WYC-323 76.0 WYC-324 85.1WYC-325 74.2 WYC-326 73.4 WYC-327 75.7 WYC-329 94.5 WYC-330 79.0 WYC-33196.0 WYC-332 55.9 WYC-333 69.1 WYC-334 80.6 WYC-335 86.9 WYC-336 86.7WYC-337 87.5 WYC-338 69.0 WYC-341 87.0 WYC-342 77.6 Tazarotene 67.6Bexarotene 63.3

The test result of inhibition rate on tumor-repopulating cells of B16-F1melanoma showed that most compounds showed significant inhibitoryactivity on tumor growth at a concentration of 10M, such as compoundWYC-103 (86.8%), WYC-207 (92.5%), WYC-209 (98.8%), WYC-209A (98.9%),WYC-209B (98.7%), WYC-212 (93.2%), WYC-217 (90.3%), WYC-218 (90.4%),WYC-329 (94.5%), WYC-331 (96.0%) etc., the corresponding colony tumorbasically did not grow or grew very slowly. The results were not only insharp contrast to the negative control group, but also reached orexceeded the inhibitory activity of the positive drugs of Tazarotene(67.6%) and Bexarotene (63.3%) on colony tumor growth.

A dose-response curve study of the inhibition on tumor growth was thenperformed on the compounds which exhibited significant inhibitoryactivity on tumor growth in the primary screening test. The colony tumorwhich was administered at an equivalent gradient was fixed, the nuclearwas stained with DAPI, the volume was measured, the inhibition rate wascalculated and regression of the dose-response curve was performed, ithad been confirmed that the compounds with better activity includedWYC-103, WYC-209, WYC-320, WYC-329, WYC-331, the ICso values of whichwere shown in Table 3 below.

TABLE 3 IC₅₀ of the compound against tumor-repopulating cells of B16-F1melanoma Inhibition rate on TRCs IC₅₀ of inhibition on Compound ofB16-F1 melanoma at a TRCs of B16-F1 number concentration of 10 μM/%melanoma/μM WYC-103 86.8 1.50 WYC-107 75.0 2.12 WYC-207 92.5 3.3 WYC-20998.8 0.19 WYC-209A 98.9 0.15 WYC-209B 98.7 0.22 WYC-212 93.2 2.28WYC-320 92.6 1.65 WYC-329 94.5 0.5 WYC-331 96.0 0.017

Wherein, the inhibition and differentiation of WYC-103 and WYC-209 ontumor-repopulating cells of B16-F1 melanoma were shown in the electronmicrograph (FIG. 1, FIG. 2), In FIG. 1 and FIG. 2, cell survival wasshown by DAPI staining, apoptosis was shown by PI staining, and mergeshowed superposition of DAPI and PI staining images.

2, Inhibitory Activity of WYC-209 on the Proliferation of VariousTumor-Repopulating Cells

Many of the above compounds exhibited excellent inhibitory activity onthe proliferation of tumor-repopulating cells of B16-F1 melanoma,wherein the activity WYC-209 was particularly excellent. Therefore, wefurther studied the inhibitory activity of this compound againsttumor-repopulating cells of six other kinds of human tumor, includingA549 lung cancer cell, MCF-7 breast cancer cell, MDA-MB-435S melanomacell, A2780 ovarian cancer cell, Hs-746T gastric cancer cell, MDA-MB-231breast cancer cell.

The above cancer cells were incubated with 3D fibrin gel medium (90-Pa)for 5 days, and the desired tumor-repopulating cells were screened.Subsequently, the culture medium was respectively treated withcollagenase and neutral protease II, and the tumor-repopulating cells ofB16-F1 melanoma were released, then the obtained repopulating cells weretransferred to a freshly prepared medium to be resuspended andmaintained at single-cell state. The tumor-repopulating cells ofindividual tumor were inoculated in 3D fibrin gel medium (90-Pa) for 5days, with 0.1% DMSO as the negative control group (represented by DMSOgroup in FIGS. 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a and 8 b), thedrug-free group as vehicle control group (represented by None group inFIGS. 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a and 8 b), and the studywas performed by beginning administrating on the day 0 and the 3rd dayrespectively, and the colony tumor volume was measured and calculated.

The results showed that WYC-209 could effectively inhibit theproliferation of various tumor-repopulating cells at a concentration of1.0 μM compared with None group, which greatly blocked the growth ofcolony tumor volume, the volume of tumor colony treated with WYC-209 wasonly 25-30% of None group (FIGS. 3a, 3b, 4a, 4b , 5 a, 5 b, 6 a, 6 b, 7a, 7 b, 8 a and 8 b, drug9# in FIGS. 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a,7b, 8a and 8 b refers to WYC-209). When the concentration of WYC-209 wasincreased to 10 μM, the proliferation of the above six kinds oftumor-repopulating cells was inhibited at a higher level, and the volumeof colony tumor was even less than 10% of the volume of None group.Especially for Hs-746T, WYC-209 could even reverse the growth trend ofcolony tumor.

3, Inhibitory Activity of WYC-331 on the Proliferation of VariousTumor-Repopulating Cells

WYC-331 exhibited excellent inhibitory activity on the proliferation oftumor-repopulating cells of B16-F1 melanoma. Next, we studied theinhibitory activity of this compound against tumor-repopulating cells ofA2780 ovarian cancer and MDA-MB-231 breast cancer.

The above human tumor cells were incubated with 3D fibrin gel medium(90-Pa) for 5 days, and the desired tumor-repopulating cells werescreened. Subsequently, the culture medium was respectively treated withcollagenase and neutral protease II, and the tumor-repopulating cells ofB16-F1 melanoma were released, then the obtained repopulating cells weretransferred to a freshly prepared medium to be resuspended andmaintained at single-cell state. The tumor-repopulating cells of B16-F1melanoma were inoculated in 3D fibrin gel medium (90-Pa) for 5 days,with 0.1% DMSO as the negative control group (represented by DMSO groupin FIGS. 9a and 9b ), the drug-free group as vehicle control group(represented by None group in FIGS. 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a,7b, 8a and 8 b), and the study was performed by beginning administratingon the day 0 and the 3rd day respectively, and the colony tumor volumewas measured and calculated, beginning administrating from the 3rd dayat a concentration of 0.1 μM, 1.0 μM, and 10 μM respectively, the colonytumor volume was measured and calculated.

The results showed that WYC-331 could completely inhibit theproliferation of tumor-repopulating cells of A2780 ovarian cancer andMDA-MB-231 breast cancer at a concentration of 10M, which greatlyblocked the growth of colony tumor volume, the volume of colony tumor ofWYC-331 was only 10-15% of None group. As for tumor-repopulating cellsof MDA-MB-231 breast cancer, WYC-331 could even reverse the growth trendof colony tumor (FIGS. 9a and 9b , wherein #31 refers to WYC-331).Meanwhile, it had been found from cell staining study that colony tumorcells inhibited by WYC-331 remained survival, and cell apoptosisappeared among only a few cells.

4, Toxicity of WYC-209 and WYC-331

The 3T3 mouse embryonic fibroblast cells and B16-F1 melanoma cells wereused as the model to study in vitro toxicity of WYC-209 and WYC-331respectively. The effect of compound WYC-209 and WYC-331 on theproliferation of 3T3 mouse embryonic fibroblast cells and B16-F1melanoma cells were studied at a concentration of 10M. The resultsshowed that WYC-209 did not affect the proliferation of 3T3 mouseembryonic fibroblast cells, and did not induce apoptosis of these cells;meanwhile, WYC-209 could significantly block the growth of colony tumorcells of melanoma, and significant cell apoptosis appeared within 6-48hours. The results showed that WYC-209 had a certain specificity fortumor-repopulating cells of melanoma, a weak effect on normal cells andless cytotoxicity (FIGS. 10a and 10b ).

Under the same condition, WYC-331 strongly inhibited the proliferationof B16-F1 melanoma cells, but did not exhibit significantapoptosis-inducing effect on 3T3 mouse embryonic fibroblasts cells andB16-F1 melanoma cells. The results showed that WYC-331 also had acertain specificity for tumor-repopulating cells of melanoma, andobvious cytotoxicity had not been observed, but the mechanism of actionthereof might be different from WYC-209 (FIGS. 11a and 11b ).

5, Inhibitory Activity of WYC-103 on Subcutaneous Transplantation Tumorof Melanoma

A subcutaneous implantation model of B16-F1 melanoma in immunocompetentmice (C57BL/6, female, 6-8 weeks) was established to study theinhibitory activity of compound WYC-103 on the tumor in situ. Firstly,B16-F1 cells were incubated within 3D fibrin gel (90-Pa in gelstiffness) that was immersed in culture medium for 5 days, and thedesired tumor-repopulating cells were screened. Subsequently, theculture medium was respectively treated with collagenase and neutralprotease II, and the tumor-repopulating cells of B16-F1 melanoma werereleased, then the obtained repopulating cells were transferred to afreshly prepared medium to be re-suspended and maintained at single-cellstate.

Six immunocompetent mice were randomly divided into two groups whichwere respectively the treatment group and the DMSO negative controlgroup. Mice were subcutaneously injected with 30,000 tumor-repopulatingcells of melanoma to establish a subcutaneous implantation model ofmelanoma. Subsequently, Mice were administered via tail vein injectionbased on the body weight and the blood volume of the mice. From day 0,mice in the treatment group were administrated with WYC-103 once every 2days at a blood concentration of 10 μM and fed normally, observing thesurvival of the mice. The results were shown below. After 19 daysexperiment, the volume of the subcutaneous melanoma in the treatmentgroup was significantly smaller than that of the DMSO control group.According to the statistical analysis, the tumor volume in the treatmentgroup was only 50% of the control group (FIG. 12).

This experiment was repeated in order to further confirm the inhibitoryactivity of WYC-103 on subcutaneous implantation tumor of B16-F1melanoma. In the present experiment, 18 immunocompetent mice (C57BL/6,female, 6-8 weeks) were randomly divided into three groups which wererespectively the treatment group, the positive control group (BMS-453was used as the positive drug) and the DMSO negative control group.Subsequently, Mice were administered via tail vein injection based onthe body weight and the blood volume of the mice. From day 0, mice inthe treatment group were administrated with WYC-103 once every 2 days ata blood concentration of 10 μM; mice in the positive control group wereadministered with BMS-453 (WYC-114) as the positive drug in the sameroute of administration; mice in the negative control group wasadministered with 0.1% DMSO in a same route of administration.

On the 20th day from the beginning of the experiment, all the mice inthe positive control group died. On the 26th day from the beginning ofthe experiment, 50% of the mice in the treatment group and the negativecontrol group died. According to the statistical analysis, the tumorvolume of the mice in the treatment group was only 50% of the negativecontrol group, and the growth of the subcutaneous implantation tumor ofthe mice in the treatment group was significantly inhibited. The studyof the body weight of the mice showed that the body weight of the micein the treatment group was stable and balanced, and there was no obvioustoxic side effects (FIG. 13, wherein drug3# refers to WYC-103, drug14#refers to BMS-453). The body weight of the mice in the positive controlgroup was significantly reduced, which indicated that there was agreater toxic side effect in the individual; while the body weight ofthe mice in the negative control group had a significant increase due tolarge tumor volume (FIG. 14). Further dissection experiment of the micein each group showed that a large number of abnormal foamy structureappeared in the peritoneal cavity of the dead mice in the positivecontrol group, which might be the cause of death in this group. Noabnormalities were found in the abdominal cavity of the mice in thetreatment group and the negative control group. This experiment showedthat WYC-103 was much better than BMS-453 in terms of the efficacy andoverall toxic side effects of the inhibition on the melanoma in situ.

6, Inhibitory Activity of WYC-103 on Metastatic Melanoma in the Lung

A metastatic melanoma model in the mouse was established to studywhether WYC-103 could inhibit metastatic melanoma in the lung thusprevent secondary tumorigenesis. Firstly, 12 normally immunocompetentmice (C57BL/6, female, 6-8 weeks) were randomly selected and injectedvia the tail vein with 3000 tumor-repopulating cells of melanoma toestablish a metastatic melanoma model in the mouse. The model mice wererandomly divided into two groups which were respectively the treatmentgroup and the negative control group. The mice were administered withWYC-103 (the treatment group) and DMSO (the negative control group) viatail vein injection once every 2 days at a blood concentration of 10 μMbased on the body weight and the blood volume of the mice.

On the 29th day of the experiment, the first dead mouse in the negativecontrol group appeared. For the convenience of comparison, killing onemouse in the treatment group, the dissection showed that obvious tissueof metastatic melanoma in the lung appeared in the dead mouse in thenegative control group, while the lung tissue of the mouse in thetreatment was normal. On the 35th day of the experiment, the second deadmouse in the negative control group appeared, and a large number oftissue of metastatic melanoma in the lung appeared in the mouse in thenegative control group, while the lung tissues of the correspondingmouse in the treatment group was normal. On the 37th day of theexperiment, 3 more mice died in the negative control group, and only 1mouse remained alive in the negative control group; then all the mice inboth groups were killed and dissected. According to the dissectionresults, metastatic melanoma appeared in the tissues of the lungs in 3mice in the negative control group, while the lung tissues of all themice in the treatment group was normal.

According to the statistical analysis, metastatic melanoma appeared inthe tissues of the lungs in 5 mice among the 6 mice in the negativecontrol group, which were all dead, only one mouse remained alive andhealthy; while the lung tissues of all the 6 mice in the treatment groupwas healthy and intact and there were no signs of metastatic melanoma,indicating preventing the occurrence of metastatic melanoma with 100%efficiency. Meanwhile, according to statistical analysis, the averagelung weight of the mice in the treatment group was only ⅓ of thenegative control group (FIGS. 15a, 15b, 15c, 15d, 15e and 15f , “+” inFIGS. 15e and 15f refers to metastasis, and “−” refers to nometastasis).

This experiment showed that WYC-103 could effectively preventrepopulating cells of melanoma from metastasizing to the lung to formsecondary lung tumor at a blood concentration of 10M, and there was noobvious toxic side effects accompanied with WYC-103 during the wholeexperiment. So WYC-103 was expected to be further used for theprevention and treatment of human metastatic cancer.

7, Inhibitory Activity of WYC-209 on Metastatic Melanoma in the Lung

This experiment was performed to study whether WYC-209 could inhibit themetastasis of melanoma to the lung thus prevent secondary tumorigenesis.The B16-F1 cells were incubated with 3D fibrin gel medium (90-Pa) for 5days, and the desired tumor-repopulating cells were screened.Subsequently, the culture medium was respectively treated withcollagenase and neutral protease II, and the tumor-repopulating cellswere released, then the obtained repopulating cells were transferred toa freshly prepared medium to be re-suspended and maintained atsingle-cell state. Then 24 immunocompetent mice (C57BL/6, female, 6-8weeks) were randomly selected and divided into three groups which wererespectively low-dose group (1.0 μM), high-dose group (10 μM) and DMSOnegative control group, with 8 mice per group. Subsequently, the micewere injected via the tail vein with 30,000 tumor-repopulating cells ofmelanoma to establish a B16-F1 metastatic melanoma model in the mouse.Subsequently, Mice were administered via tail vein injection based onthe body weight and the blood volume of the mice. From the 5th day on,mice in the treatment group were administrated with WYC-209 once every 2days at a blood concentration of 1.0 μM and 10 μM; mice in the DMSOgroup was administered with 0.1% DMSO in a same route of administrationas negative control. At this time, there was no significant differencein the body weight between the groups, the mice were fed normally,observing the survival of the mice.

On the 23th day of the experiment, the first dead mouse (the lung tissuethereof was shown in FIG. 16a , No. 8) in the DMSO group appeared. Onthe 30th day, all the remaining mice were killed. Obvious tissue ofmetastatic melanoma appeared in the lungs of 6 mice among the 8 mice inthe DMSO group, and there was no abnormalities found in the liver andstomach (referring to FIG. 16a , No. 1-7). During the same period (thenight of the 29th day), one mouse died in the 1.0 μM treatment group(the lung tissue refers to FIG. 16b , No. 8); the metastatic melanomaappeared in the tissues of lungs of 4 mice among the 8 mice in the 1.0μM treatment group, and there was no abnormalities found in the liverand stomach (FIG. 16b , No. 1-7 showed the lung tissue on the 30th day).During the same period, the metastatic melanoma appeared in the tissuesof the lungs of only one mouse among the 8 mice in the 10 μM treatmentgroup, and there was no abnormalities found in the liver and stomach. Onthe 30th day, 6 mice (75%) in the DMSO group suffered pulmonarymetastatic melanoma, 4 mice (50%) in the 1.0 μM treatment group sufferedpulmonary metastatic melanoma, and 1 mouse (12.5%) suffered pulmonarymetastatic melanoma in the 10 μM treatment group only (referring to FIG.16c , wherein No. 1-5 showed the lung tissue on the 30th day, and No.6-8 showed the lung tissue on the 29th, 24th, 20th day respectively).There was a statistically significant difference among the lung tissueweight of the mice in each group, the DMSO group >1.0 μM treatmentgroup >10 μM treatment group (“+” refers to metastasis, “−” refers to nometastasis in FIGS. 16a, 16b and 16c ).

This experiment showed that WYC-209 could prevent repopulating cells ofmelanoma from metastasizing to the lung to form secondary lung tumorwith 50% efficiency at a blood concentration of 1.0M, and with 87.5%efficiency at a blood concentration of 10.0 μM. The DMSO group showed75% mortality rate of metastatic melanoma in the lung. WYC-209 exhibitedan excellent activity of inhibiting and even healing secondarytumorigenesis in the immunocompetent mice in vivo. Meanwhile, there wasno obvious toxic side effects accompanied with WYC-209 during the wholeexperiment, so WYC-209 was expected to be further used for theprevention and treatment of various primary or metastatic cancers.

In summary, the above in vitro activity experiments showed that WYC-103,WYC-209 and WYC-331 had strong inhibitory activity againsttumor-repopulating cells of melanoma, the IC₅₀ reached 0.45 μM, 0.25 μMand 0.017 μM respectively. WYC-209 had strong inhibitory activityagainst A549 lung cancer cells, MCF-7 breast cancer cells, MDA-MB-435Smelanoma cells, A2780 ovarian cancer cells, Hs-746T gastric cancercells, MDA-MB-231 breast cancer cell.

In vivo activity experiments showed that WYC-103 had a strong inhibitoryactivity on subcutaneous transplantation tumor of melanoma in mice, thetumor volume was only 50% of the control group at a concentration of 10μM. WYC-103 and WYC-209 inhibited the metastasis of repopulating cellsof melanoma to the lung with 100% and 87% efficiency at a concentrationof 10 μM respectively, which could bring new treatment for preventionand treatment of metastasis of human tumor.

It had been confirmed from In vitro experiment that WYC-209 and WYC-331had no effect on the growth of 3T3 cell clones and could not induceapoptosis of 3T3 cells. Meanwhile, WYC-103 and WYC-209 exhibited highlysafety in the in vitro and in vivo experiments. From the abovebiological study embodiments, the compounds of the present inventionprovided new possibilities for the prevention and treatment of leukemia,lymphoma, primary solid tumors and metastatic tumors.

It is to be understood that the foregoing description of two preferredembodiments is intended to be purely illustrative of the principles ofthe invention, rather than exhaustive thereof, and that changes andvariations will be apparent to those skilled in the art, and that thepresent invention is not intended to be limited other than expressly setforth in the following claims.

1.-14. (canceled)
 15. A compound represented by formula I, anenantiomer, a diastereomer or a pharmaceutically acceptable saltthereof,

wherein, U is CR^(9a) or N; V is CR^(9b) or N; X is CR^(9c) or N; W isCR^(9d) or N; in the definition of U, V, X and W, each of R^(9a),R^(9b), R^(9c) and R^(9d) is independently hydrogen, hydroxy, nitro,cyano, halogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted with halogen, C₁-C₆alkoxy, —NR¹⁰R¹¹,

or —COOR¹⁴; each of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently hydrogenor C₁-C₆ alkyl; A, E, G together with Z form the ring selected from thegroup consisting of

each of R², R³ and R⁵ is independently hydrogen, hydroxy, halogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₁-C₆ alkyl substituted with halogen, C₁-C₆alkoxy, C₁-C₆ acyl, C₆-C₁₀ aryl or “C₃-C₆ heteroaryl having 1 to 2heteroatoms selected from the group consisting of oxygen, sulfur andnitrogen”; m is 0, 1, 2 or 3; when there are more than one substituentsof R¹, the substituents are identical or different; R¹ is hydrogen,hydroxy, nitro, cyano, halogen, C₁-C₆ alkyl, C₁-C₆ alkyl substitutedwith halogen, C₁-C₆ alkoxy, —NR⁶R⁷ or —COOR⁸; each of R⁶, R⁷ and R⁸ isindependently hydrogen or C₁-C₆ alkyl; Y is —CN, —COOR¹⁵ or —CO₂NHR¹⁶;each of R¹⁵ and R¹⁶ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl or C₁-C₆ alkylacyl.
 16. The compound represented by formula I asdefined in claim 15, wherein, when each of R², R³ and R⁵ isindependently halogen, the “halogen” is fluorine, chlorine, bromine oriodine; when each of R², R³ and R⁵ is independently “C₁-C₆ alkyl”, the“C₁-C₆ alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl or hexyl; when each of R², R³ and R⁵ is independently“C₂-C₆ alkenyl”, the “C₂-C₆ alkenyl” is vinyl or propenyl; when each ofR², R³ and R⁵ is independently “C₁-C₆ alkyl substituted with halogen”,the “C₁-C₆ alkyl substituted with halogen” is trifluoromethyl; when eachof R², R³ and R⁵ is independently “C₁-C₆ alkoxy”, the “C₁-C₆ alkoxy” ismethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, pentoxy or hexoxy; when each of R², R³ and R⁵ isindependently “C₁-C₆ acyl”, the “C₁-C₆ acyl” is acetyl or formyl; wheneach of R², R³ and R⁵ is independently “C₆-C₁₀ aryl”, the “C₆-C₁₀ aryl”is phenyl; when each of R², R³ and R⁵ is independently “C₃-C₆ heteroarylhaving 1 to 2 heteroatoms selected from the group consisting of oxygen,sulfur and nitrogen”, the “C₃-C₆ heteroaryl having 1 to 2 heteroatomsselected from the group consisting of oxygen, sulfur and nitrogen” ispyridinyl or pyrimidinyl; when R¹ is “halogen”, the “halogen” isfluorine, chlorine, bromine or iodine; when R¹ is “C₁-C₆ alkyl”, the“C₁-C₆ alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl or hexyl; when R¹ is “C₁-C₆ alkyl substituted withhalogen”, the “C₁-C₆ alkyl substituted with halogen” is trifluoromethyl;when R¹ is “C₁-C₆ alkoxy”, the “C₁-C₆ alkoxy” is methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy orhexoxy; when each of R⁶, R⁷ and R⁸ is independently “C₁-C₆ alkyl”, the“C₁-C₆ alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl or hexyl; when each of R^(9a), R^(9b), R^(9c) andR^(9d) is independently “halogen”, the “halogen” is fluorine, chlorine,bromine or iodine; when each of R^(9a), R^(9b), R^(9c) and R^(9d) isindependently “C₁-C₆ alkyl”, the “C₁-C₆ alkyl” is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;when each of R^(9a), R^(9b), R^(9c) and R^(9d) is independently “C₁-C₆alkyl substituted with halogen”, the “C₁-C₆ alkyl substituted withhalogen” is trifluoromethyl; when each of R^(9a), R^(9b), R^(9c) andR^(9d) is independently “C₁-C₆ alkoxy”, the “C₁-C₆ alkoxy” is methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxyor hexoxy; when each of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently“C₁-C₆ alkyl”, the “C₁-C₆ alkyl” is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, pentyl or hexyl; when each of R¹⁵ and R¹⁶is independently “C₁-C₆ alkyl”, the “C₁-C₆ alkyl” is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;when each of R¹⁵ and R¹⁶ is independently “C₂-C₆ alkenyl”, the “C₂-C₆alkenyl” is vinyl or propenyl; when each of R¹⁵ and R¹⁶ is independently“C₁-C₆ acyl”, the “C₁-C₆ acyl” is formyl or acetyl.
 17. The compoundrepresented by formula I as defined in claim 15, wherein, one, two,three, or four of U, V, X and W is N atom, or U is CR^(9a), V isCR^(9b), X is CR^(9c), and W is CR^(9d).
 18. The compound represented byformula I as defined in claim 17, wherein, when two of U, V, X and W areN atoms, the compound represented by formula I is selected from thegroup consisting of

or, when one of U, V, X and W is N atom, the compound represented byformula I is

or, when U is CR^(9a), V is CR^(9b), X is CR^(9c), and W is CR^(9d), thecompound represented by formula I is as compound F,

in the definition of compound F, one, two, three, or four of R^(9a),R^(9b), R^(9c) and R^(9d) is not hydrogen.
 19. The compound representedby formula I as defined in claim 18, wherein, in compound A, when Y is—COOR¹⁵, R¹⁵ is hydrogen or ethyl; and/or, in compound A, A, E, Gtogether with Z form

and/or, in compound B, when Y is —COOR¹⁵, R¹⁵ is methyl or ethyl;and/or, in compound B, A, E, G together with Z form

and/or, in compound C, when Y is —COOR¹⁵, R¹⁵ is hydrogen or ethyl;and/or, in compound C, A, E, G together with Z form

and/or, in compound D, when Y is —COOR¹⁵, R¹⁵ is hydrogen or ethyl;and/or, in compound D, A, E, G together with Z form

and/or, in compound E, Y is CN; and/or, in compound E, A, E, G togetherwith Z form

and/or, in compound F, when Y is —COOR¹⁵, R¹⁵ is hydrogen, methyl orethyl; and/or, in compound F, A, E, G together with Z form the ringselected from the group consisting of


20. The compound represented by formula I as defined in claim 15,wherein, the compound represented by formula I is selected from thegroup consisting of


21. A preparation method for the compound represented by formula I asdefined in claim 15, which comprises conducting a coupling reaction withcompound II and III to give compound I;

wherein, X¹ is halogen.
 22. A compound represented by formula II, III,IV or V,

wherein, A, E, G, Z, R¹, m, Y, U, V, X and W are as defined in claim 15;X¹ is halogen; X² is halogen.
 23. A method for treating a patient inneed of a medicament for treating a primary tumor, comprisingadministering to the patient a medicament comprising an effective amountof the compound represented by formula I, the enantiomer, thediastereomer or the pharmaceutically acceptable salt thereof as definedin claim
 15. 24. A method for treating a patient in need of a medicamentfor preventing and/or treating a metastatic tumor, comprisingadministering to the patient a medicament comprising an effective amountof the compound represented by formula I, the enantiomer, thediastereomer or the pharmaceutically acceptable salt thereof as definedin claim
 15. 25. A method for treating a patient in need of a medicamentfor preventing and/or treating leukemia and/or lymphoma, comprisingadministering to the patient a medicament comprising an effective amountof the compound represented by formula I, the enantiomer, thediastereomer or the pharmaceutically acceptable salt thereof as definedin claim
 15. 26. A method for treating a patient in need of a medicamentfor treating the disease selected from the group consisting of animalfetal growth, internal environment stability, vision, morphogenesis,skin aging and cell differentiation control, comprising administering tothe patient a medicament comprising an effective amount of the compoundrepresented by formula I, the enantiomer, the diastereomer or thepharmaceutically acceptable salt thereof as defined in claim
 15. 27. Apharmaceutical composition, which comprises the compound represented byformula I, the enantiomer, the diastereomer or the pharmaceuticallyacceptable salt thereof as defined in claim 15, and a pharmaceuticallyacceptable carrier.